Biochem. J. (2013) 449, 319–331 (Printed in Great Britain) doi:10.1042/BJ20120957 319

REVIEW ARTICLE Evolution of intracellular compartmentalization Yoan DIEKMANN*† and Jose´ B. PEREIRA-LEAL*1 *Instituto Gulbenkian de Ciencia,ˆ Rua da Quinta Grande 6, 2780-156 Oeiras, Portugal, and †Programa de Doutoramento em Biologia Computational (PDBC), Instituto Gulbenkian de Ciencia,ˆ Rua da Quinta Grande 6, 2780-156 Oeiras, Portugal

Cells compartmentalize their biochemical functions in a variety compartments from each of these three categories, membrane- of ways, notably by creating physical barriers that separate based, endosymbiotic and protein-based, in both prokaryotes and a compartment via membranes or proteins. Eukaryotes have a eukaryotes. We review their diversity and the current theories and wide diversity of membrane-based compartments, many that controversies regarding the evolutionary origins. Furthermore, are lineage- or tissue-specific. In recent years, it has become we discuss the evolutionary processes acting on the genetic increasingly evident that membrane-based compartmentalization basis of intracellular compartments and how those differ across of the cytosolic space is observed in multiple prokaryotic lineages, the domains of life. We conclude that the distinction between giving rise to several types of distinct prokaryotic organelles. eukaryotes and prokaryotes no longer lies in the existence of a Endosymbionts, previously believed to be a hallmark of compartmentalized cell plan, but rather in its complexity. eukaryotes, have been described in several bacteria. Protein-based compartments, frequent in bacteria, are also found in eukaryotes. Key words: endosymbiont, intracellular compartmentalization, In the present review, we focus on selected intracellular organelle.

“Nothing epitomizes the mystery of life more than the Organelles are important cellular structures that perform spatial organization and dynamics of the cytoplasm.” many essential functions. They allow multiple biochemical Tim Mitchison [1] environments to coexist in the cell and to be adapted independently INTRODUCTION [10]. For example, proteins can be translated and degraded at the same time without undesired cross-talk [11]. Moreover, Elaborate and dynamic spatial organization is a ubiquitous spatial confinement of toxic metabolites limits the propagation of property of living matter and the key to life’s distinct condition potential damage. [2]. Spatial structure is most apparent in the form of separate In the present paper, we consider the evolution of organelles compartments or compartmentalization, a phenomenon studied and physical compartmentalization. Our main aim is to discuss in its abstraction as ‘modularity’ in diverse fields ranging from how new organelles are formed and new organellar functions psychology to engineering, from arts to biology [3]. evolve. To do so, we illustrate the broad diversity of organelles In biology, modular or compartmentalized systems are found and contrast the various mechanisms of compartmentalization across all scales. The separation of functions inherent to in prokaryotes and eukaryotes (Figure 1). We review current compartmentalization results in robust [4] yet evolvable [5] theories about the origins and evolution of different types of systems, which may explain the prevalence and evolutionary organelles. Finally, we briefly discuss the genetic basis of different success of this organizational paradigm: ecological networks are compartments, i.e. the pathways for assembly, maintenance, compartmentalized, individuals are composed of multiple parts inheritance, transport from/to and across the physical barriers, such as organs, organs are composed of multiple cell types, and the evolutionary mechanisms shaping those genetic cells themselves are subdivided into compartments, proteins are systems. composed of domains, and so on. The tremendous diversity of organelles precludes an exhaustive Among these entities, the cell plays a special role in biology and enumeration, as well as an in-depth discussion of each one in has for long time been understood as the basic unit from which all particular. Instead, we chose to focus on selected compartments living beings are built (the ‘Cell Theory’; see [6] for a historical which illustrate distinct aspects, and point the reader to recent perspective). The cell compartmentalizes processes in multiple reviews for deeper exploration of this fascinating topic. ways, e.g. by using gradients [7], via lateral diffusion barriers such as the septins in membranes [8], by bringing multiple reactions

together via protein–protein interactions as for example in EVOLUTION OF ORGANELLES: PICTURES, REACTIONS AND GENES Biochemical Journal www.biochemj.org metabolic channelling [9], or by using membranes and proteins to physically separate distinct areas within the cell. Hereinafter, we How many types of organelles are there? How do they arise? loosely refer to physically delimited compartments as organelles, These are old and surprisingly difficult questions, tightly linked the focus of the present review. to the emergence of cell biology itself.

Abbreviations used: BMC, bacterial microcompartment; DCG, dense-core granule; EGT, endosymbiotic gene transfer; ER, endoplasmic reticulum; ES, endomembrane system; IFT, intraflagellar transport; IMS, internal membrane system; LRO, lysosome-related organelle; MB, magnetotactic bacteria;MRO, mitochondria-related organelle; NE, nuclear envelope; NPC, nuclear pore complex; TGN, trans-Golgi network; TIC, transporter of the inner chloroplast membrane; TIM, transporter of the inner mitochondrial membrane; TOC, transporter of the outer chloroplast membrane; TOM, transporter of the outer mitochondrial membrane. 1 To whom correspondence should be addressed (email [email protected]).

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Not surprisingly, comparative genomics has its own limitations. The starting point for a comparative genomic study is always a set of sequenced and annotated genomes. As sequencing is biased towards organisms of biomedical or industrial interest, many evolutionarily interesting taxa are not represented by a single sequenced genome. The second step in comparative genomics is the selection of genes that are informative about a given organelle. As we will see below, a significant fraction of organellar diversity is not associated to any molecular data that can be mapped to a genome and, as a result, comparative genomics is simply impossible. Having genomes to compare, and representative genes selected, the homology between genes need to be established. For closely related organisms, this is a rather simple task. However, after hundreds of millions of years, the evolutionary relationships may be less obvious. After establishing homology, the potential gene content of ancestral hypothetical species lying on the interior branching points of the species tree can be reconstructed. This is mostly done using parsimony, a straightforward application of Occam’s razor. In brief, the ancestral state is chosen which requires the fewest evolutionary events that alter its gene content (i.e. gene gains and losses) to explain its descendants. However, there is no Figure 1 Diversity of physically delimited compartments intrinsic reason why evolution would have to always proceed parsimoniously, i.e. in a minimal number of steps, and statistically Examples of membranous and proteinaceous organelles in the prokaryotic and eukaryotic more sophisticated model-based approaches exist. Lastly, the domain with their taxonomic distribution. Shown are the nucleus (IMS/Eukarya), bacterial interpretation of the results requires judging the cell-biological thylakoids (inspired by the model presented in [74]) (IMS/Bacteria), a granule which has consistency of the comparative genomics predictions [17]. There been proposed to represent an organelle homologous with acidocalcisomes (the broken-line circles represent the cell wall and plasma membrane) [159] (IMS/Archaea), a mitochondrion is no general recipe to do so, and any reasoning depends on what is (Endosymbiotic/Eukarya), a Gammaproteobacterial endosymbiont of a Betaproteobacteria living known about the cell biology of the compartment. Reconstructing in cells of the mealy bug (the outer broken-line circle represents the plasma membrane, and the evolution of organelles is thus a perilous adventure. However, the inner broken-line circle represents the outer membrane of the mealy bug’s endosymbiotic as we discuss below, a series of general principles regarding the compartment) [122] (Endosymbiotic/Bacteria), the eukaryotic vault protein complex [131,132] origins and evolution of intracellular compartments are emerging. (Proteinaceous/Eukarya), a model for the shell of BMCs [77] (Proteinaceous/Bacteria), and For practical reasons, we divide the discussion into three types of finally archaeal gas vesicles [127,163] (Proteinaceous/Archaea). To the best of our knowledge, no endosymbiont living in an archaea has been described to date. Furthermore, the existence of a organelles: IMSs (internal membrane systems), endosymbiotic membrane delimiting the archaeal granule has to be confirmed (indicated by the question mark). and protein-based organelles. The presence of vaults in Excavata is inferred from our own BLAST analysis retrieving putative homologues of the major vault protein in Kinetoplastida; however, cell biological evidence is required (again indicated by a question mark). INTERNAL MEMBRANE SYSTEMS As early as the 19th Century, light microscopy had shown The characteristic cellular architecture of eukaryotes is defined the existence of the nucleus, ER (endoplasmic reticulum) or by extensive membrane-delimited compartments. In animals, ‘ergatoplast’, Golgi, mitochondria and chloroplasts [6]. Yet, approximately half of the volume of a eukaryotic cell is the full extent of eukaryotic cellular complexity was only membrane-enclosed (see Table 12.1 in [18]), and in plants revealed with the advent of electron microscopy in mid-20th the vacuole can make up to 95% of the cellular volume. Century [12]. In parallel, biochemical fractionation led to the Prokaryotes also have unique and diverse membranous organelles discovery of other compartments such as the peroxisome and compartmentalizing the cytoplasmic space [19] (Figure 2). the lysosome [13,14]. Most importantly, biochemical approaches allowed the assignment of specific biochemical activities to distinct organelles, establishing the notion of biochemical or functional compartmentalization of the cell. The eukaryotic ES (endomembrane system) Microscopy showed very early on that similar compartments The eukaryotic ES is composed of numerous organelles, such were present in many organisms. For example, the early Cell as the ER, the Golgi apparatus, lysosomes or vacuoles, and a Theory postulated that all plants, and later also all animals, were trafficking machinery that links these compartments via vesicular composed of nucleated cells (reviewed in [6,12]), and fuelled the intermediates. It is functionally organized mainly along two major first debates about the origins and inheritance of an organelle pathways: the secretory/exocytic pathway that synthesizes, folds, [15,16]. modifies and targets proteins and lipids to the plasma membrane Besides morphological and functional similarity, comparative or the outside of the cell [20], and the endocytic pathway which genomics has recently opened a new window that allows for operates in the opposite direction, taking proteins and material up the comparison of the genetic basis of organelles. The steady from the surface in order to be either recycled or degraded [21]. growth of fully sequenced genomes and the accumulation of The ES probably evolved from inward budding of the plasma data that map organellar functions to gene products allows us membrane in some ancestor of eukaryotes [22]. The main support to ask whether two organelles are homologous, because they are for this hypothesis comes from the location of the protein built from homologous gene products, or whether the apparent translocation machinery, a system to integrate or translocate similarity is based on entirely different machineries, suggesting a proteins into or across lipid bilayers and which is a fundamental functional and/or morphological analogy instead. requirement for all autonomous lifeforms. In prokaryotes, it is

c The Authors Journal compilation c 2013 Biochemical Society Evolution of intracellular compartmentalization 321 found in the plasma membrane, whereas eukaryotes translocate As it is not implausible to think that eukaryogenesis involved proteins through the membrane of the ER. major population bottlenecks, non-selective processes may also Depending on the cellular complexity ascribed to the eukaryotic explain the evolution of some of the eukaryotic cellular structures. ancestor, eukaryotes are an example either for an increase in As a consequence, although the emergence of complex features compartmentalization or even for the de novo evolution of inspires us to think of selective drives, many of the features of an ES in an ancestral cell previously lacking membranous the eukaryotic ES, and of the nucleus in particular, may have compartments. This directly prompts an essential question: what started as non-adaptive events. These would have been fixed as a are the evolutionary forces which can lead to autogenous evolution consequence of small population sizes, and only later gained the of compartments? essential functions that ensured their conservation in eukaryotes.

The autogenous versus exogenous debate: peroxisomes Evolving a compartmentalized cell plan: the nucleus Compartments can evolve in different ways: autogenously, as we In this section, we discuss possible evolutionary forces driving discuss above for the nucleus, or as a result of an endosymbiotic organellogenesis. We illustrate the debate using the example event. For most organelles, both scenarios have been proposed, but of the eukaryotic nucleus, which is the defining morphological in many cases the debate has settled: the community mostly agrees feature shared by all eukaryotic cells and the organelle that has on an endosymbiotic origin of mitochondria and an autogenous, spurred the most debate. The nucleus is a specialized compartment i.e. non-endosymbiotic, origin of the ES. spatially confining the chromosomal DNA and consists of the However, for example, in the case of the peroxisome, deciding double bilayered NE (nuclear envelope), a specialized part of between the two competing models of compartmental origin is not the ER. Nuclear pores fenestrate the NE and are the sole sites straightforward, and owing to its hybrid characteristics, arguments of material exchange, which are filled and stabilized by one of in favour of both modes of origin persist. Peroxisomes are the largest macromolecular assemblies of the eukaryotic cell, the single-membrane-bound organelles characterized by the presence NPC (nuclear pore complex). of hydrogen-peroxide-producing oxidases, and catalases that The question of how the nucleus evolved has attracted break down hydrogen peroxide [33]. In animals, peroxisomes much attention, as it has to be explained by any scenario for are involved in lipid metabolism and free radical detoxification eukaryogenesis. Multiple models based on endosymbiosis, either [34], among other processes. In protists, the diversity and of viral [23] or prokaryotic organisms [24], as well as autogenous specializations of their functions sometimes blurred their common origins in the context of an evolving ES have been proposed and identity as peroxisomes, and motivated names such as glycosome, extensively debated [17,25,26]. Although this debate surely is not glyoxysome or Woronin body [35]. over yet, recent evidence strongly supports an autogenous origin An endosymbiotic origin of peroxisomes is suggested by (see [27] for a recent review). several lines of evidence. Peroxisomal membrane and matrix In any case, the origin of the nucleus does not explain why it proteins are translated by free cytosolic ribosomes independently evolved in the first place. In the following, we highlight some of the ER, and their import into the peroxisome is mediated suggestions for an adaptive value early in the origin of the by short peroxisome-targeting signals [33], which are bound by nucleus. Lopez-Garcia and Moreira [28] propose a scenario in cytosolic receptors. Such ER-independent protein translation and which the formation of the nucleus is initially driven by the targeting mechanisms are also found in mitochondria and plastids, need to separate the anabolic and catabolic pathways. Hence with which peroxisomes share certain metabolic pathways. this hypothesis states that the enclosing of the genome is Peroxisomes normally arise from fission of existing peroxisomes, a by-product of metabolic compartmentalization. In contrast, an inheritance strategy shared with endosymbiotic organelles. other theories place the adaptive value on the informational However, this model has recently been challenged by function of the nucleus. Cavalier-Smith [29] hypothesized that both genomic [36] and cell-biological [37] evidence. Comparative as chromosomes became longer, the nucleus emerged to provide genomic analysis of peroxisomal proteomes revealed that physical protection against chromosome shearing. Jekely´ [30] approximately half of the genes are of eukaryotic origin. proposed that the nucleus allowed the cell to avoid the formation of Furthermore, mechanisms for the recruitment of entire less efficient chimeric ribosomes resulting from mixing ribosomal mitochondrial pathways have been proposed [36,38], able to subunits in the chimaeric proto-eukaryote. Another scenario account for the presence of the bacterial genes in the peroxisomal argues for the separation between DNA transcription in the proteome. Particularly relevant is that the import machinery used nucleus and RNA translation in the cytoplasm as a central by peroxisomes has been found to share similarities with the driver for compartmentalizing the genetic material. Assuming an ER misfolded protein machinery. More generally, peroxisomal early origin of mitochondria, such a separation would provide maintenance proteins were found to be homologous with the a mechanism allowing for (slow) splicing to occur before ERAD (endoplasmic-reticulum-associated protein degradation) translation, important to cope with an invasion of introns in the pathway [34,36], suggesting an evolutionary connection between wake of the acquisition of mitochondria [31]. This latter view peroxisomes and the ER and hence to the ES. A second major line is not inconsistent with the other scenarios, and has also been of evidence supporting an autogenous origin of the peroxisome suggested as a later drive for nuclear evolution in [28]. Thus these relates to its inheritance. Besides fission, peroxisomes can be three models argue that fidelity and efficiency of information formed de novo [34] from membranes and vesicles clearly processing provided the basic selective drive to form an NE. originating from the ER [33]. Hence current evidence strongly An alternative to the above is to view the nucleus as a ‘frozen supports an autogenous origin. accident’, using the words of Bill Martin [26]. The smaller the population size, the weaker is the force of selection in relation to drift. This opens the possibility that characters which are not One organelle, many shapes: Golgi advantageous in any way, or even slightly deleterious, can be fixed. Organelles of the ES mostly have complex shapes, with spherical, It has been argued that this basic principle is able to account for flat or tubular regions, and the tendency of these shapes to be much of the genomic architecture observed in eukaryotes [32]. conserved throughout evolution suggests that they are important

c The Authors Journal compilation c 2013 Biochemical Society 322 Y. Diekmann and J. B. Pereira-Leal

Figure 2 Ultrastructure of selected prokaryotic compartments

Illustrations of the structural and taxonomic diversity of prokaryotic intracellular compartments. 1, Archaeal gas vesicles. Taken from Springer, Complex Intracellular Structures in Prokaryotes, 2006, 115–140, Gas vesicles of archaea and bacteria by Pfeifer, F., Figure 4(A), c 2006 Springer-Verlag, Berlin, with kind permission from Springer Science and Business Media. 2, An archaeal granule which has been proposed to be homologous with acidocalcisomes (Acidocalcis., uncertainty indicated by question mark). The arrow indicates the electron-dense volutin granule. Reproduced with permission from Seufferheld, M.J., Kim, K.M., Whitfield, J., Valerio, A. and Caetano-Anolles, G. (2011) Evolution of vacuolar proton pyrophosphatase domains and volutin granules: clues into the early evolutionary origin of the acidocalcisome. Biol. Direct 6, 50. 3, Isolated chlorosomes (photosynthetic membranes) from Acidobacteria. From Bryant, D.A., Costas, A.M., Maresca, J.A., Chew, A.G., Klatt, C.G. et al. (2007) Candidatus Chloracidobacterium thermophilum: an aerobic phototrophic Acidobacterium. Science 317: 523–526. Reprinted with permission from AAAS. 4, Thylakoid membranes with perforations, as well as carboxysomes. Scale bar, 500 nm. Reprinted by permission from Macmillan Publishers Ltd: EMBO J., Nevo, R., Charuvi, D., Shimoni, E.,

c The Authors Journal compilation c 2013 Biochemical Society Evolution of intracellular compartmentalization 323 for organelle function [39]. Yet, organelle structure can be very lysosomal membrane proteins delivered by endosomes coming dynamic and vary across organisms and tissues. The Golgi from the TGN [49]. apparatus is an example of such a dynamic and morphologically The lysosome is a good example of an evolutionarily plastic heterogeneous compartment. compartment which evolved additional functions. In fungi and The Golgi is the central hub of the membrane-trafficking plants, the functional equivalent of the lysosome is the vacuole, system and the site where the two major pathways, secretory which has adapted to many additional roles, e.g. in calcium and endocytic, intersect. It receives secretory lipids and proteins homoeostasis and osmotic control, long-distance transport of from the ER, which are post-translationally modified, sorted nutrients through the mycelial filaments, storage of organic and and targeted to their final destination. Vesicles for constitutive inorganic nutrients, and in generating turgor pressure [50–52]. In secretion are formed at a specialized subcompartment of the plants, at least three distinct vacuole types have been described, Golgi, the TGN (trans-Golgi network). the lytic, protein storage and the senescence-associated vacuole The Golgi is nearly ubiquitous in eukaryotic cells [40] that coexist in some cell types [53,54]. and performs essential functions. Yet, it shows great diversity In animals, the lysosome diversified into a whole family of in biogenesis, morphology and inheritance. In mammals, it distinct compartments, the LROs (lysosome-related organelles) consists of a series of flattened cisternal membrane structures [55]. Some LROs evolved to function as secretory compartments, responsible for the Golgi’s large and regular structure. The yet without losing the ability to perform classic lysosomal cisternae form Golgi stacks, which are interconnected by functions, as for example the lysosomes of cytotoxic T- lateral tubules and organize into the Golgi ribbon [41]. At the lymphocytes. In contrast, other LROs have lost degradative onset of mitosis, the Golgi loses its characteristic shape and capacity and coexist with lysosomes in one cell, e.g. melanosomes fragments into tubulovesicular structures, which are partitioned and diverse types of granules. They are still formed from maturing during cytokinesis and later reform the Golgi [42]. Interestingly, endosomes, and are therefore distinct compartments different Drosophila cells usually lack a Golgi ribbon, but clearly have the from other organelles involved in regulated secretion such as potential to form it, as is observed for example in spermatids secretory granules. LROs and lysosomes are biogenically related [41]. In Saccharomyces cerevisiae, the Golgi does not have organelles [56], suggesting an ‘organelle paralogy’ that still awaits the stacked morphology, but rather consists of single isolated confirmation at the genetic level. LROs are highly taxon- and cisternae distributed throughout the cytoplasm [43]. However, tissue-specific, and with growing knowledge of the diversity of this type of organization appears to be an exception, as most eukaryotic cell biology more of these organelles may be found. fungi possess Golgi stacks [43,44]. Yet another shape is observed A candidate LRO is for example the apicomplexan rhoptry, an in plants: their Golgi apparatus is made of hundreds of individual apical secretory organelle involved in host cell invasion [57]. motile stacks which are not disassembled during cell division [45]. Most surprising for an organelle with essential functions, the Golgi has been lost altogether on at least eight independent Homology versus analogy: granules and bacterial occasions [44]. For example, the protozoan parasite Giardia intracytoplasmic membranes lamblia lacks a morphologically discernible Golgi, and secretory Functional and/or morphological similarity is most readily functions are performed at specific ER sites [46]. explained by homology, i.e. common ancestry. Thus the common interpretation of similarities observed among organelles is that of a single evolutionary origin. However, convergent evolution also plays a role in subcellular evolution, giving rise to analogous One organelle, many functions: lysosomes organelles defying this interpretation. Below, we discuss two Lysosomes are the primary catabolic site of the animal cell [47] examples: DCGs (dense-core granules), which probably arose that receive and degrade macromolecules from multiple cellular multiple times in eukaryotes, and the relationship between the pathways (secretory, endocytic, autophagic and phagocytic) IMSs of Plantomycetes and those of eukaryotes. [48] in their characteristic acidic lumen. The maintenance of DCGs are specialized secretory vesicles with a characteristic lysosomal function depends on constant influx of hydrolases and condensed protein core involved in regulated secretion [58,59].

Schwarz, R., Kaplan, A., Ohad, I. and Reich, Z. (2007) Thylakoid membrane perforations and connectivity enable intracellular traffic in cyanobacteria. EMBO J. 26, 1467–1473, c 2007. 5, Thylakoids and carboxysomes in a dividing cell. Scale bars: left, 200 nm; right, 50 nm. From Kerfeld, C.A., Sawaya, M.R., Tanaka, S., Nguyen, C.V., Phillips, M., Beeby, M. and Yeates, T.O. (2005) Protein structures forming the shell of primitive bacterial organelles. Science 309, 936–938. Reprinted with permission from AAAS. 6, Chlorosomes in a cell with a central inclusion. Taken from Springer, Photosynthesis Research, 86, 2005, 145–154, The ultrastructure of Chlorobium tepidum chlorosomes revealed by electron microscopy, by Hohmann-Marriott, M.F., Blankenship, R.E. and Roberson, R.W., Figure 1B, c 2005 Springer, with kind permission from Springer Science and Business Media. 7, A Gammaproteobacterial endosymbiont (γ -prot.) living in a Betaproteobacterial host, itself an endosymbiont of the mealy bug. b, bacteria; hc, host cell cytoplasm; im, inner membrane; om, outer membrane; ss, symbiotic sphere (white arrows indicate the three membranes of the sphere). Scale bar, 0.0706 μm. Reprinted by permission from Macmillan Publishers Ltd: Nature, von Dohlen, C.D., Kohler, S., Alsop, S.T. and McManus, W.R. (2001) Mealybug β-proteobacterial endosymbionts contain γ -proteobacterial symbionts. Nature 412, 433–436, c 2001. 8, Intravacuolar Betaproteobacterial endosymbiont (β-prot.) living in a Gammaproteobacterium. IVS, intravacuolar structures. Reprinted with permission from Larkin, J.M. and Henk, M.C. (1996) Filamentous sulfide-oxidizing bacteria at hydrocarbon seeps of the Gulf of Mexico, Microscopy Research and Technique, 33, 23–31. c 1996 Wiley-Liss, Inc. 9, BMC, originally called an enterosome (arrowhead) [77]. From Applied and Environmental Microbiology, 2001, 67, 5351–5361, 10.1128/AEM.67.12.5351.5361.2001. Reproduced with permission from American Society for Microbiology. 10, Chromatophores (photosynthetic membranes). B, poly-β-hydroxybutyrate granules; C, ribosome-containing cytoplasm; CM, cytoplasmic membrane; N, nucleoplasm with DNA threads; P, polyphosphate granule; Th, thylakoid; ZW, cell wall. The arrow shows the site of cytoplasmic membrane invagination. Taken from Springer, Archiv fur¨ Mikrobiologie, 59, 1967, 385, Thylakoidmorphogenese bei Rhodopseudomonas palustris, Tauschel, H.D. and Draws, G., with kind permission from Springer Science and Business Media. 11, Bacterial acidocalcisomes. The arrow indicates a vacuole, containing an electrondense material in the periphery. Scale bar, 0.1 μm. Reproduced from Seufferheld, M., Vieira, M.C., Ruiz, F.A., Rodrigues, C.O., Moreno, S.N. and Docampo, R. (2003) Identification of organelles in bacteria similar to acidocalcisomes of unicellular eukaryotes. J. Biol. Chem. 278, 29971–29978. c 2003 The American Society for Biochemistry and Molecular Biology. 12, Magnetosomes with empty membranous vesicles (MV). Scale bar, 250 nm. From the Journal of Bacteriology, 1988, 170, 834–841, reproduced with permission from American Society for Microbiology. 13, Internal membranes forming a compartment claimed to resemble the eukaryotic nucleus. ICM, intracytoplasmic membrane; N, nucleoid; NE, nuclear envelope; P, paryphoplasm. Republished with permission of Annual Reviews, Inc., from Intracellular compartmentation in plantomycetes, by Fuerst, J.A., Annual Reviews in Microbiology 59, 299–328, 2005; permission conveyed through Copyright Clearance Center, Inc.

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Membranous compartments resembling mammalian DCG are shown in Figure 2: 4 and 5 show thylakoids, 3 and 6 show found in diverse eukaryotic lineages where they serve a wide range chlorosomes, and 10 shows chromatophores). They form a of functions, e.g. the trichocysts in Paramecium tetraurelia,which proper compartment with characteristic lipid composition [71,72] function in predator defence, or encystation secretory vesicles harbouring the photosynthetic systems in Cyanobacteria and in G. lamblia, which provide protection from the environment chloroplasts. In Cyanobacteria, they mainly consist of long [60]. They share important hallmarks with mammalian granules: lamellae appearing as several flattened and stacked layers. biosynthesis from the TGN, subsequent maturation and regulated Unlike bacteria performing anoxygenic photosynthesis, thylakoid secretion upon specific stimuli [60]. The comparison of the membranes are not connected to the plasma membrane [72]. molecules essential for the structural scaffold of DCG in ciliates The discontinuity with the plasma membrane raises an and mammals showed that the genes in ciliates are lineage-specific important question: the precursors of the photosystems are pre- innovations. Moreover, key proteins important for maturation, assembled in the plasma membrane, but how are those proteins e.g. endoproteases, and organellar identity, e.g. SNAREs (soluble and lipids transferred to the thylakoids? The obvious possibilities N-ethylmaleimide-sensitive fusion protein-attachment protein are via transient membrane connections or by vesicle transport receptors) and Rabs, are not orthologous. Hence, comparative [71,73], but the definitive mechanism has not yet been determined. genomics hints at an independent origin of DCG at least in Interestingly, cytoplasmic vesicles have been reported in fixed ciliates and mammals, implying that an entire organelle can arise samples of some cyanobacterial species, where they were found repeatedly by convergent evolution. to be located near and partially fused to thylakoids [74]. This Another important debate regarding homology versus analogy means that bacteria with thylakoids may be capable of long- is the relationship between the intracytoplasmic membranes range vesicular trafficking, but independent confirmation is still of Planctomyetes (see, for example, 13 in Figure 2) and the lacking. In support of this hypothesis, thylakoid membranes eukaryotic ES, in particular the nucleus. Planctomycetes are showed numerous perforations through which substantial flow of a major bacterial phylum that compartmentalize cytoplasmic cellular material such as ribosomes and storage granules could be space by internal membranes [61]. In its simplest form, e.g. observed. These features could be adaptations to allow for efficient in the genus Pirellula, a lipid bilayer sequesters chromosomes intracellular transport, possibly also of membrane-bound vesicles and ribosomes from other cellular components and forms an [74]. Hence this could mean that when confronted with the organelle coined the pirellulosome [62]. In some Planktomycetes, corresponding cell-biological challenge, prokaryotes may have the pirellulosome is itself compartmentalized and contains a the potential to evolve an ES organized according to the same double-bilayer membrane fenestrated by small pore-like openings principles as eukaryotes. surrounding the compacted chromosome [63]. These membranes hence form a structure with obvious morphological parallels to the Lateral organelle transfer: bacterial magnetosomes eukaryotic nucleus, although the functional implications of those IMSs are currently unclear. For example, a clear separation of Magnetosomes are membranous compartments of a diverse transcription and translation cannot be observed, as ribosomes paraphyletic group of MB (magnetotactic bacteria) (see, for are present both inside and outside the nuclear body [64]. example, 12 in Figure 2). They are usually organized in one The discovery of membrane coat-like proteins in these bacteria or more chains of 15–20 organelles. They allow the sensing of [65], the description of endocytosis-like processes [66] and geomagnetic field lines, which bacteria use to find preferred redox several other similarities to eukaryotes have fuelled speculations conditions [64]. Magnetosomes are formed by invaginations of the that Plantomycetes may represent a frozen intermediate stage plasma membrane [75] which house a ∼50 nm magnetic crystal. between prokaryotes and eukaryotes [67]. This interpretation They contain a characteristic set of proteins in various quantities, has, however, been strongly opposed [68]. This is a situation which suggests the existence of a dedicated sorting pathway [76]. that exemplifies well the limitations of comparative genomics: The arrangement in chains is achieved by filaments formed by the claims of homology of some components rely on very homologues of eukaryotic actin. Hence magnetotactic bacteria sensitive methods to identify distant relationships, necessarily provide an example for prokaryotes, which, like eukaryotes, use susceptible to false positive errors. Carl Sagan popularized the the cytoskeleton to position their organelles within the cell and idea that “extraordinary claims require extraordinary evidence”, actively shape and maintain their intracellular organization [64]. considering the time that separates us from these events, any Sequencing of several MB revealed that most of the genes claim of homology based on remote similarities is to be treated believed to be involved in biogenesis and functioning of with caution. magnetosomes are comprised within a large genomic island [76a], which may be sufficient to form a magnetosome [64]. It could be shown by comparative genomics that the island has been laterally Thylakoids, bacterial intracellular trafficking? transferred between diverse bacterial species [76b] accounting for Planctomycetes provide a good illustration of the fact that the patchy phylogenetic distribution of MB. bacteria are able to evolve IMSs fully detached from the plasma Thus magnetosomes are an example for the lateral transfer of membrane. Yet, a major difference from the eukaryotic ES is an entire compartment. This process is unique to the prokaryotic the lack of obvious vesicular trafficking, conceptually separating domain, where it may be rather common: comparative genomics the endomembranes observed across the two domains of life. suggests that, for example, the proteinaceous compartments Bacteria do not share the same need for active trafficking as discussed below have been laterally transferred among as much eukaryotes, as they are in general small enough to rely on diffusion as one-fifth of sequenced bacterial species [77]. [69]. However, some use motor-driven intracellular transport for cellular movement [70] and indications exist that some cyanobacteria may have evolved dynamic vesicular trafficking ORGANELLES OF ENDOSYMBIOTIC ORIGIN pathways in the context of thylakoid membranes. The thylakoids are one of at least three major types of The universal mitochondria photosynthetic membranes [64] (examples of thylakoids and One of the most distinctive features of eukaryotic cells, and the other two types, chlorosomes and chromatophores, are potentially the critical step in the establishment of the eukaryotic

c The Authors Journal compilation c 2013 Biochemical Society Evolution of intracellular compartmentalization 325 cell plan [78], is the presence of mitochondria. They are the Parasites versus endosymbionts result of an ancient endosymbiosis predating the radiation of Mitochondria and chloroplasts represent one extreme of full eukaryotes, as all eukaryotic cells have mitochondria or MROs integration between endosymbiotic organelle and host. At the (mitochondria-related organelles) such as hydrogenosomes or opposite end of the spectrum are compartments formed by mitosomes [79–81]. This second group is sometimes genome- intracellular parasites that invade and parasitize eukaryotic cells less, but biochemical similarity and molecular composition have for several resources, occupying different intracellular niches established them as derived mitochondria ([82], and reviewed (phagosomes, lysosomes, cytosol, etc.) and having a deleterious in [80,81]). In most cases, mitochondria and MRO seem to effect on the host [94–96]. Examples are the agents of Lyme be involved in the generation of ATP, either by aerobic or disease, typhus or leprosy. In between these two extremes, we anaerobic respiration [79]. Sometimes, this function may be find multiple independent cases of endosymbiosis of bacteria from shared with other prokaryote-derived organelles, such as in ciliates diverse taxonomic groups with various degrees of integration with living under anaerobic conditions, which have acquired multiple organisms from the majority of eukaryotic taxa. archaeal endosymbionts that consume produced hydrogen and use It is unclear where to draw the line between parasite it to reduce carbon dioxide [83]. These observations have fuelled and endosymbiont. In the case of the associations of the hypothesis that mitochondria provided the energy necessary Buchnera sp. with several insects, the endosymbiont supplies the for the establishment of the complex eukaryotic cell plan [78]. host cell with essential amino acids that it cannot synthesize or However, the only mitochondrial function that is never lost, even obtain from the environment, and its presence has no obvious in very derived MRO, is the synthesis of iron–sulfur clusters fitness cost, suggesting (endo)symbiosis [97]. On the other hand, [80,84]. This suggests that the dependence of the cell on the the association of Wolbachia with several insects is less clear: energy produced by mitochondria may be reduced, for example it provides protection against viral and bacterial infections, in the context of parasitic relationships. while inducing a series of reproductive alterations on the host organisms via feminization, male-killing, parthenogenesis and/or cytoplasmic incompatibility [98]. Hence fitness trade-offs exist and the distinction between parasite and symbiont is less obvious. However, unlike Buchnera, Wolbachia is not essential, suggesting Same organelle, repeatedly: plastids that the parasite has not fully integrated with the host. It is tempting to speculate that endosymbiotic compartments may start Plastids are found in a variety of phylogenetic lineages. However, off as a parasitic relationship that evolved to mutual benefit, to the their evolutionary relationships are not straightforward, as point where the endosymbiont becomes an essential compartment successive endosymbiotic events resulted in cells consisting of of the host cell. Endosymbiotic associations have been reviewed several nested organisms. extensively elsewhere [99–104]. A single ancient endosymbiosis gave rise to the chloroplasts found in the Plantae supergroup (Glaucophyte, and red and green algae) (reviewed in [85–87]). This stable relationship was established between a putative phagotropic mitochondria- Moving genes and proteins around: EGT (endosymbiotic containing host cell and a cyanobacterium. Subsequent gene transfer) independent symbiotic events of chloroplast-containing algae Endosymbiotic and obligate endoparasitic relationships are with several protozoa gave rise to the plastids found in accompanied by extensive gene loss, as these bacteria ‘outsource’ Chromalveolata, Rhizaria and Excavata (see [85–88] for reviews). many of their normal metabolic requirements to the host [100]. These secondary endosymbioses are well illustrated by the Endosymbionts such as Carsonella rudii exemplify how far this existence of typically four plastid membranes, as opposed genome miniaturization can go, retaining only 182 open reading to the two membranes observed in organelles derived from frames and a 160 kb genome [105]. Genes from the bacterial a primary endosymbiosis (mitochondria and chloroplasts). endosymbiont are frequently transferred to the nucleus, and Furthermore, in Dinoflagellates, even tertiary endosymbiotic infrequently retained. For example, Wolbachia-derived transfers events have occurred, leading to organisms with an intriguingly of various sizes have been detected in a large range insects and complex compartmentalized cell plan [86]. Interestingly, the nematodes, ranging from individual genes to almost complete amoeba Paulinella chromatophora acquired a cyanobacterial genomes [106]. endosymbiont which has been argued to represent a second In the case of the mitochondria and chloroplasts, this genome independent origin of a primary plastid. It is, however, still a reduction has been even more extreme and was accompanied by a matter of debate whether the level of genetic integration [89] and substantial transfer of the organelle’s genes to the nuclear genome the protein-targeting system [90] qualify the endosymbiont as a and by the loss of the corresponding genes from the organelle bona fide organelle [91]. genome. This led to a reliance on the host to synthesize the gene Primary plastids (chloroplasts) are photosynthetic organelles products and target them to the symbiont, requiring the evolution that can differentiate in a reversible manner into storage functions. of targeting and transport systems. This process is termed EGT Some secondary plastids retained their photosynthetic function, (reviewed in [107]), and was argued to represent the defining step as, for example, is the case for members of the genus Euglena, in the transition from an endosymbiont to an organelle (for a while others lost it (see [88] for a review). The function of discussion, see [108]). these latter plastids is unclear, even though their existence in Mitochondrial proteins are synthesized in the cytosol and human pathogens as, for example, the causative agents of malaria, maintained in an unfolded translocation-ready conformation by toxoplasmosis and cryptosporidiosis has made them subject of the action of chaperones. Their import into mitochondria is intense interest (see [92,93] for reviews). Thus plastids represent mediated by the TIM (transporter of the inner mitochondrial mem- yet another example of one organelle with multiple taxon-specific, brane)–TOM (transporter of the outer mitochondrial membrane) cell-type-specific and condition-specific functions, illustrating complexes via sophisticated pathways (reviewed extensively in how the principle discussed for lysosomes applies also to [109]). Proteins destined to the plastid are mostly synthesized organelles of endosymbiotic origin. in the cytosol and targeted to the TIC (transporter of the inner

c The Authors Journal compilation c 2013 Biochemical Society 326 Y. Diekmann and J. B. Pereira-Leal chloroplast membrane)–TOC (transporter of the outer chloroplast origins of some or even most of the prokaryotic endosymbionts membrane) complexes. These complexes are molecularly of bacteria. unrelated to each other, suggesting independent evolutionary origins. Bacteria contain many proteins with similarity to the mitochondrial translocation and targeting machineries, suggesting PROTEIN-BASED ORGANELLES that the latter were assembled from the former [110,111]. Similarly, the TIM–TOM system appears to have evolved from Although the creation of physical separation between two pre-existing prokaryotic and eukaryotic components [112]. environments has been most visibly achieved by lipid membranes, Interestingly, a subset of proteins that are destined to the both prokaryotes and eukaryotes have also used proteins for the chloroplast are also trafficked through the ES, by an as yet same purpose. unknown mechanism [113–115]. This has been hypothesized to represent an ancient transport pathway, which appeared before the establishment of the TIC–TOC pathway [87]. Supporting this Protein shells everywhere argument is a recent endosymbiosis of a Cyanobacteria by the Prokaryotes possess a variety of protein-bound organelles. These amoeba P. chromatophora [116] (reviewed in [86–88]), where compartments present a relatively recent paradigm of prokaryotic several genes suffered EGT [89], and some have been shown organization, and few of these organelles have been studied to be translated in the amoeba’s cytosol and then transported to thoroughly. Better known are for example gas vesicles found in the endosymbiont in a Golgi-mediated pathway [90]. There is archaea (see, for example, 1 in Figure 2) and bacteria [127], and a growing evidence that mitochondria can sort material into and certain class of BMCs (bacterial microcompartments) defined by from vesicles that are then transported to peroxisomes (reviewed homologous shell protein families which we discuss below. in [117]). Recent work revealed further that oxidized proteins can BMCs are a widely distributed functionally diverse organelle be trafficked from mitochondria to the lysosome via vesicular family which is defined by its characteristic proteinaceous shell intermediates [118]. Thus, although bona fide organelles have [77]. The shell is assembled from a few thousand members evolved specific targeting and transport systems, these coexist of the conserved BMC family of shell proteins, giving rise with vesicle-mediated transport. It is interesting to note that the to organelles up to ∼150 nm in size. Some BMCs store ES is frequently subverted by intracellular pathogens [119,120], special compounds [128], whereas others create an internal supporting the notion that endosymbiosis may, in some cases, microenvironment in which metabolic enzymes and auxiliary derive from a parasitic association. proteins are concentrated. This enhances the catalytic efficiency by enabling substrate channelling and due to increased local metabolite concentrations which help to overcome poor enzyme affinities for their substrate, or serves to spatially confine toxic Prokaryotes inside prokaryotes or volatile intermediates [77]. First described in 1956 [128a], Less appreciated than endosymbiosis between pro- and eu- BMCs have long been studied mostly by electron microscopy, karyotes is the fact that bacteria have also found replication niches which makes it difficult to estimate their abundance and diversity inside other prokaryotes, which lends support to the idea that throughout bacteria. Examples of BMCs include carboxysomes the endosymbiotic event that resulted in mitochondria did not (see, for example, 4 and 5 in Figure 2), which can be necessarily require a pre-existing ES. One type of bacteria that found in all Cyanobacteria and concentrate Rubisco (ribulose- contain prokaryotic endosymbionts are Gammaproteobacterial 1,5-bisphosphate carboxylase/oxygenase), the Pdu compartment Beggiatoa spp. (8 in Figure 2), sulfide-oxidizing organisms, found in Salmonella enterica (see, for example, 9 in Figure 2) found in freshwater and marine habitats. They harbour a variety or the Eut microcompartment also found in Escherichia coli. of prokaryotic endosymbionts, but the metabolic nature of Relatively little is known about the cell biology of this special the relationship is still elusive [121]. A better studied case class of organelles. A basic challenge is the sorting of enzymes to is a secondary endosymbiosis in the endosymbiont of the the interior of the protein shell. Most interestingly, in Salmonella, mealy bug (7 in Figure 2). This nested constellation consists short N-terminal targeting signals have been described that are of a Gammaproteobacteria living as an endosymbiont of a sufficient to direct proteins to the lumen of these organelles [129]. Betaproteobacteria, which in turn is an endosymbiont of an Thus proteinaceous organelles can employ a system analogous to insect, the mealybug [122]. Genomic analysis revealed extreme the targeting system known from secretion in bacteria and the two metabolic integration between the two endosymbionts, with major types of lipid-bound organelles in eukaryotes. the Gammaproteobacteria complementing several amino acid Recent molecular characterization of the shell proteins allowed biosynthetic pathways of the Betaproteobacteria [100]. Even the computational screening of bacterial genomes, which revealed mitochondria have been targeted by other prokaryotes, such homologous domains in more than 400 or one-fifth of the as ‘Candidatus Midichloria mitochondrii’, an endosymbiont of sequenced bacteria analysed [77]. The phylogenetic distribution the tick Ixodes ricinus. Although it resides in the cytosol, suggests frequent horizontal gene transfer of BMC shell genes, it can invade and replicate inside mitochondria and consume which are organized in gene clusters facilitating their modular them [123,124]. transfer. It could be shown by the artificial expression of an Our understanding of the associations between prokaryotes empty microcompartment in E. coli that the genetic information is still in its infancy. We do not know how frequent they in such a cluster is indeed sufficient for the formation of BMCs are, the type of metabolic trade-offs they may involve or [130]. how inheritance of the endosymbiont is achieved after division Although less known, eukaryotes also have protein of the host cell. Furthermore, the entry mechanisms involved shells forming small organelles, termed ‘vaults’. Vaults are in these associations remain to be determined. They may be ribonucleoprotein particles consisting of two identical cups, each similar to those used by the Deltaproteobacteria endoparasite with a characteristic eight-fold symmetrical shell structure. They Bdellovibrio bacteriovorus that invades and replicates inside other sequester an interior volume large enough to capture hundreds of bacteria [125]. Bacterial predators are, in fact, quite frequent proteins and multiple copies of small RNAs [131], and are found and phylogenetically widespread [126], and could represent the mostly in the cytoplasm, although some localize to the nucleus

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Figure 3 Evolutionary processes shaping the genetic basis of an organelle, illustrated using the nucleus as an example

Evolutionary processes which have the potential to alter the set of genes underlying an organelle. In a given structure, these processes do not exclude each other. Examples of nuclear genes which probably evolved following the corresponding process, taken from [153], are given. FG repeat, phenylalanine–glycine repeat; GP210, glycoprotein 210; HGT, horizontal gene transfer; NTF2, nuclear transport factor 2.

[132]. Homologues of the highly conserved vault constituents not form cilia [146]. The integration of cilia with other transport can be found in diverse eukaryotes [133], and occur in numbers systems has become even more apparent with the discovery that potentially as high as 104–107 per cell [134]. Since their discovery ciliary entry of KIF17 (kinesin family member 17), an IFT motor, in 1986 [134a], several putative functions have been put forth, e.g. is regulated by importin-β2 and RanGTP [147], key regulators of roles in multidrug resistance, signalling and innate immunity, but nucleocytoplasmic transport. their exact function remains elusive. The vault shell has been Thus the cilium represents an alternative way to create a shown to be dynamic, opening the possibility that the vault’s distinct compartment within the ES. Although its biogenesis interior may be able to interact functionally with the rest of and maintenance, like that of all other organelles within the ES, cell [135]. requires the sorting and targeting of components using vesicular intermediates, the physical separation of the space is not achieved by enclosing it in a membrane, but rather by different protein- Protein-based compartments in the ES: eukaryotic cilium based macromolecular machinery. Above, we discussed the integration between the endosymbiotic organelles and the ES. Now, we turn to the cilium in order THE MOLECULAR BASIS OF ORGANELLAR EVOLUTION to illustrate the integration of different types of organelles, proteinaceous and membranous. We refer the reader to several The ability to sustain a compartmentalized cell plan in general, and reviews on the functions and structure of the cilium and its any one organelle in particular, requires molecular machinery for connection to the centrosome [136–138]. its assembly, maintenance, inheritance and for diverse trafficking The eukaryotic cilium or flagellum (we use these terms routes. We discuss commonalities and major differences of how interchangeably) is a microtubule-based protrusion from the these pathways evolved at the molecular level, both between plasma membrane that is templated by a mostly invariant nine-fold eukaryotes and prokaryotes, as well as between the different symmetrical microtubule-based cylinder termed the basal body, types of organelles. from which the axoneme protrudes. Active-transport mechanisms In eukaryotes, organelles of the ES usually share a conserved involving molecular motors move microtubule subunits and core of genes throughout all lineages which is complemented by membrane receptors within, into and out of the cilium in a highly lineage-specific genes. This pattern arises from the interplay of dynamic process. At the base of the cilium are protein-based two opposing evolutionary forces: lineage-specific gene losses physical barriers that separate an internal and external space, as and gains. Genes gained in specific lineages mostly derive well as protein-based physical barriers preventing lateral diffusion from two processes: co-option of previously unrelated genes of proteins in the plasma membrane [136,139–141]. Cilia are and paralogous expansion of protein families already involved found in all eukaryotic groups, and are thus believed to pre-date with the organelle (see, for example, [148,149]). Co-opted genes the radiation of eukaryotes (reviewed in [141]). themselves can originate from different sources: they can be The cilium appears to be a unique organelle in having internal endosymbiotic, horizontally transferred or the result of gene microtubules. However, it has many connections to the ES. duplication. The second process contributing lineage-specific The set of molecular motors which regulate the process of genes is paralogous expansion, which happens frequently and IFT (intraflagellar transport) [142,143] within the cilium are is the result of gene duplications followed by preservation of homologous with those functioning in endomembrane trafficking. both duplicates mostly due to sub- or neo-functionalization [150]. The assembly of axonemes and delivery of receptors to the ciliary Co-option and duplication are not the only possibilities for the membrane depends on polarized trafficking. Cargo destined emergence of lineage-specific genes. Other possibilities are the for the cilium is assembled and sorted at the Golgi and delivered at de novo origin of genes and domain shuffling, i.e. the evolution the flagellar base, in a process dependent on canonical regulators of new genes by combining pre-existing protein domains in new of trafficking in the ES (reviewed in [139,144]). This has led to ways [151,152]. All of these possibilities have been shown to the proposal that cilia represent an elaboration of a pre-existing have contributed genes forming the NE and the NPC [153] polarized trafficking from the Golgi to the plasma membrane (Figure 3). Gene duplications may be particularly important for [145]. This hypothesis is supported by the discovery that IFT the functional diversification and evolution of new organelles components are required for polarized secretion in cells that do in eukaryotes. For example, the organellar paralogy model

c The Authors Journal compilation c 2013 Biochemical Society 328 Y. Diekmann and J. B. Pereira-Leal proposes that duplication/divergence of the key gene families of trafficking exists. Endosymbiosis is apparently the exception an organelle could give rise to new organelles, free to diverge and rather than the rule in prokaryotes, whereas endosymbionts acquire new functions analogous to the process at the gene level are ubiquitous in eukaryotes which all have at least one, [154]. the mitochondrion or MROs. Furthermore, prokaryotes tend In endosymbiotic organelles of eukaryotes, the driving force to have one type of compartment and not the coexistence seems to be genome reduction by extensive gene loss [100,155]. of multiple organelles that characterizes eukaryotes. Thus, One extreme case is observed in human mitochondria, which although the presence of intracellular compartments no longer have only 13 protein-coding genes. Although only one genome distinguishes prokaryotes from eukaryotes, the complexity of of a prokaryotic endosymbiont of prokaryotes has been well the compartmentalized cell plan is still substantially higher in characterized, it suggests that genome reduction is also observed eukaryotes. [100]. Inheritance of mitochondria involved the co-option of the Under this scenario, the debate on the origins of eukaryotes machinery that insures segregation of the ES to the daughter needs to be formulated differently: what is the reason for the divide cells after division [156]. More recent endosymbionts may have in complexity between the eukaryotic and prokaryotic cell plan? also followed the same route, as exemplified by Wolbachia’s It has been proposed that energy limitations in prokaryotes may segregation to the centrosome during cell division and its constrain their genome size and therefore preclude the evolution microtubule-based inheritance [157]. of a more complex compartmentalized cell [78]. Under this The molecular machineries underlying prokaryotic membrane- scenario, the acquisition of mitochondria was thus the key step based organelles as well as protein-based compartments are still en route to the more complex eukaryotic cell plan. This suggests poorly understood. However, in addition to the mechanisms an intrinsic limit to the complexity of extant compartmentalized described for eukaryotes, a different process is important: prokaryotes. Yet, notably this lack of complexity has not limited horizontal transfer of entire genomic islands containing the the success of prokaryotes, which are clearly the dominant genes necessary to form a compartment. This appears to be lifeform on our planet. In contrast, eukaryotes appear to be a frequent event both for membranous organelles, such as ‘condemned’ to a compartmentalized cell plan, which may at magnetosomes, and proteinaceous organelles such as BMCs, best be slightly simplified with the loss of a small number of which are the most widely distributed form of compartment in organelles. prokaryotes. A question closely linked to the above considerations is how easy it is to evolve a compartment, and if the potential differs between the domains of life. In eukaryotes, endosymbiotic CONCLUSIONS events appear to be more frequent than in prokaryotes. However, reaching the high degree of integration, as, for example, achieved The origin of eukaryotes has been identified as one of the by mitochondria and plastids, appears uncommon even in major transitions in evolution [158]. Whereas this is frequently eukaryotes. The emergence of an ES is a rare event, having equated with the evolution of compartmentalization, the only happened once. It then served as a template to many present review hopefully contributes to raise awareness that lineage-specific organelles. This suggests that it may be simpler compartmentalization exists in all domains of life. and sufficient to build new organelles by variations of the The prokaryotic cell plan is emerging as increasingly more existing system. This is strongly supported by the examples of complex than previously thought. It is currently unclear analogous organelles within the ES [60], suggesting that evolving how widespread compartmentalization is in prokaryotes, and a compartment in response to similar challenges is possible. In how much more diversity will emerge from broader sampling contrast, different IMSs exist in multiple independent prokaryotic of the prokaryotic world. In particular, the extent of lineages, suggesting that these rudimentary forms are somehow compartmentalization of archaea is still largely unknown, as simpler to establish. We must then reach the conclusion that most studies have focused on bacteria (Figure 2). Especially, compartmentalization evolved independently more frequently in the discovery of archaeal compartments may have profound prokaryotes than in eukaryotes. Furthermore, in prokaryotes, the implications for our understanding of cellular evolution, as genetic clustering of some of the systems into genomic islands exemplified by recent claims that acidocalcisomes could be and the ease of lateral transfer result in frequent transfer of present in all domains of life and may thus date back as far whole organelles between species. It is interesting to note that as to the last universal common ancestor [159]. However, these overexpression of a foreign gene in E. coli has been observed to are currently speculations and other interpretations for example be enough to induce the formation of massive intracellular vesicles of eukaryotic acidocalcisomes as LROs exist [160]. [162]. Yet, as argued in [17], it remains unclear how functionless In both prokaryotes and eukaryotes, compartments come in lipid vesicles could be co-opted to form compartments without different flavours: they are bound either by membranes or by being purged by purifying selection. proteins, and can be of autogenous origin or derived from an At the molecular level, an issue that has attracted much attention endosymbiotic event. Examples for each of these classes exist in is the evolutionary relationship between genes underlying the both domains of life (Figure 1). Yet, there are clear differences different types of compartments, particularly those seemingly between the compartments in prokaryotes and eukaryotes. present in both prokaryotes and eukaryotes. Yet, most prokaryotic Eukaryotes are derived from a highly compartmentalized cell, compartments have little functional and molecular data associated frequently termed the LECA (last eukaryotic common ancestor), to them. Thus we expect that exciting findings will arise which already possessed an elaborate ES [161]. All eukaryotes from sequencing of more genomes of compartmentalized have more or less retained this complex compartmentalized prokaryotes, and from the cell-biological dissection of prokaryotic cell plan. In contrast, prokaryotic membrane organelles are compartments, potentially settling some of the debates on phylogenetically scattered and apparently evolved independently, homology. Without a better understanding of prokaryotic although potential exceptions such as acidocalcisomes exist. Also, compartments, i.e. their diversity and molecular basis, little they have not generally reached the same level independence progress is likely to be made in elucidating the most fascinating from the plasma membrane compared with their eukaryotic problems of compartmentalization, complexity and ultimately the counterparts as no definitive evidence for prokaryotic vesicular origin of eukaryotes themselves.

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Received 12 June 2012/10 September 2012; accepted 17 September 2012 Published on the Internet 14 December 2012, doi:10.1042/BJ20120957

c The Authors Journal compilation c 2013 Biochemical Society