View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Biochimica et Biophysica Acta 1822 (2012) 1326–1336 Contents lists available at SciVerse ScienceDirect Biochimica et Biophysica Acta journal homepage: www.elsevier.com/locate/bbadis Review Molecular basis of peroxisomal biogenesis disorders caused by defects in peroxisomal matrix protein import☆ Shirisha Nagotu 1, Vishal C. Kalel 1, Ralf Erdmann ⁎, Harald W. Platta ⁎ Abteilung für Systembiochemie, Medizinische Fakultät der Ruhr-Universität Bochum, D-44780 Bochum, Germany article info abstract Article history: Peroxisomal biogenesis disorders (PBDs) represent a spectrum of autosomal recessive metabolic disorders Received 19 December 2011 that are collectively characterized by abnormal peroxisome assembly and impaired peroxisomal function. Received in Revised form 26 March 2012 The importance of this ubiquitous organelle for human health is highlighted by the fact that PBDs are mul- Accepted 9 May 2012 tisystemic disorders that often cause death in early infancy. Peroxisomes contribute to central metabolic Available online 19 May 2012 pathways. Most enzymes in the peroxisomal matrix are linked to lipid metabolism and detoxification of reactive oxygen species. Proper assembly of peroxisomes and thus also import of their enzymes relies on Keywords: fi Peroxisome biogenesis disorders speci c peroxisomal biogenesis factors, so called peroxins with PEX being the gene acronym. To date, 13 Zellweger syndrome spectrum PEX genes are known to cause PBDs when mutated. Studies of the cellular and molecular defects in cells PEX derived from PBD patients have significantly contributed to the understanding of the functional role of the Peroxin corresponding peroxins in peroxisome assembly. In this review, we discuss recent data derived from both Ubiquitination human cell culture as well as model organisms like yeasts and present an overview on the molecular mech- anism underlying peroxisomal biogenesis disorders with emphasis on disorders caused by defects in the per- oxisomal matrix protein import machinery. This article is part of a Special Issue entitled: Metabolic Functions and Biogenesis of Peroxisomes in Health and Disease. © 2012 Elsevier B.V. All rights reserved. 1. Peroxisomes — general introduction Unlike in yeast and plants, β-oxidation of fatty acids occurs in both per- oxisomes and mitochondria of mammalian cells. Very long chain fatty acids, long chain dicarboxylic acids, some unsaturated fatty acids, Peroxisomes are single membrane bound, dynamic organelles of pristanoic acids, di and tri-hydroxycholestanoic acids are metabolized eukaryotic cells. They were first identified in the electron microscopy in peroxisomes. In humans, peroxisomes are also involved in synthesis images of mouse kidney cells [1]. They are mostly spherical, 0.1 to of cholesterol, bile acids and ether lipids such as plasmalogens, which ac- 1 μm in diameter and surrounded by a single lipid bilayer membrane count for the major portion of the ethanolamine glycerophospholipids in [2]. They do not contain DNA or a protein translation machinery and the adult human brain, notably 80–90% of these lipids in the white mat- hence import nuclear coded proteins synthesized in the cytosol post- ter of the brain [5–10]. Apart from the above mentioned functions, re- translationally [3]. The number, size and function of peroxisomes de- cently a role for peroxisomes in the antiviral innate immunity has been pend on the cell type or organism and the environmental conditions. described. In mouse embryonic fibroblasts and human hepatocytes, the This is also reflected by their unique variability in enzyme content antiviral signaling protein MAVS (mitochondrial antiviral-signaling pro- and thus metabolic functions, which marks them as “multi-purpose or- tein) has been localized to both peroxisomes and mitochondria. The ganelles” that adjust their metabolic capabilities according to the cellu- data demonstrate that peroxisomes provide a significant site of antiviral lar needs [4]. Until now 50 different enzymes have been identified in signal transduction and that they promote a rapid response to viral infec- the peroxisomal matrix, which are linked to different biochemical path- tion [11]. ways. However, the central function of these organelles in all instances After their initial description in 1954 [1], peroxisomes were first is β-oxidation of fatty acids and hydrogen peroxide detoxification. associated with human disease in 1973, when it was discovered that kidney and liver tissue from Zellweger syndrome patients were devoid of peroxisomes [12]. In 1984, a specific biomarker was identified [13] ☆ This article is part of a Special Issue entitled: Metabolic Functions and Biogenesis of Peroxisomes in Health and Disease. that could be used for the screening of patients and the first gene defect ⁎ Corresponding authors at: Institut für Physiologische Chemie, Ruhr-Universität associated with a peroxisomal biogenesis defect was identified in 1992 Bochum, Universitätsstr, 150, D-44780 Bochum, Germany. Tel.: +49 234 322 4943; [14]. fax: +49 234 321 4266. The finding that peroxisomes constitute the sole site for breakdown E-mail addresses: [email protected] (R. Erdmann), [email protected] (H.W. Platta). of fatty acids in fungi and the synthesis of plasmalogens in mammalian 1 Joint first authors. cells, has been used for the screening of yeast [15] and Chinese hamster 0925-4439/$ – see front matter © 2012 Elsevier B.V. All rights reserved. doi:10.1016/j.bbadis.2012.05.010 S. Nagotu et al. / Biochimica et Biophysica Acta 1822 (2012) 1326–1336 1327 ovary (CHO)-cell mutants [16] affected in peroxisome function. These PTS2). Notable exceptions are C. elegans and diatoms, which have lost mutants were instrumental for the identification of the corresponding the genes for targeting PTS2 proteins during evolution and import all genes by functional complementation which led to the discovery of matrix proteins via PTS1 signals [36,37]. the first proteins essential for peroxisome formation [17,18].Mostof PTS1 was initially discovered as the carboxyterminal tripeptide the currently known peroxisome biogenesis factors, collectively called SKL in the firefly luciferase protein [38]. Sequence comparisons be- peroxins (PEX), were identified by these genetic approaches, some tween species led to a consensus sequence (S/A/C)-(K/R/H)-(L/M) [39]. later on by proteomic approaches [19] or as in the case of the recently In recent years, it became clear that additional amino acid residues with- discovered PEX34, by their interaction with known peroxins [20]. in the cargo protein are of relevance for the interaction with the PTS1- Apart from the study of their metabolic functions another widely receptor, which led to a refinement of the definition of the PTS1 [40]. studied research area is peroxisome biogenesis. Essential aspects of ThePTS1asatargetingsignalisusedbymajorityoftheperoxisomal peroxisome biogenesis concern the cellular origin of the organelle proteins. Mammalian catalase and alanine-glyoxylate aminotransferase and the matrix and membrane protein import, which are completely are examples of two proteins that need interactions in addition to the independent processes. A role for the endoplasmic reticulum (ER) in binding of the PTS1 for proper targeting to the peroxisomes. A KANL the origin of peroxisomal membrane was hypothesized initially sequence at the C-terminus is required for the targeting of mammalian based on the close proximity of ER and peroxisomes in electron mi- catalase [41] whereas two signals are required for the targeting of crographs [21]. However the post-translational import of peroxisomal alanine-glyoxylate aminotransferase, a C-terminal KKKL and an internal proteins developed the idea of peroxisomes as an autonomous organ- eight amino acid sequence [42]. The PTS2 is located near the N-terminus elle which multiply by growth and division [22]. This concept of per- of the proteins and conforms to the motif R-(L/V/I/Q)-xx-(L/V/I/H)-(L/S/ oxisomes being autonomous organelles was challenged with the G/A)-x-(H/Q)-(L/A) [43]. Very few proteins are targeted to the peroxi- discovery that peroxisomes can be formed from the endoplasmic re- somes by PTS2 in mammals. However, in plants approximately one ticulum upon the reintroduction of Pex3 in peroxisome-deficient third of the peroxisomal proteins are targeted via the PTS2 pathway cells. [23–25]. While, the possibility of de novo formation of peroxi- [44].InSaccharomyces cerevisiae, thiolase (Fox3) and glycerol phosphate somes is now well accepted, the significance of this contribution to dehydrogenase (Gpd1) are the only proteins known to use the PTS2 the peroxisome content is still under debate. While one view is that [45,46]. all peroxisomal membrane proteins traffic via the ER [26], other Proteins that harbor a peroxisomal targeting signal are recognized work demonstrates that under wild type conditions peroxisomes by their respective receptors in the cytosol — which is Pex5 for the are generally formed by growth and division and only under circum- PTS1 [47] and Pex7 for the PTS2 import [48]. The C-terminal domain stances when there are no peroxisomes in a cell, they can be formed of Pex5 binds to the PTS1 sequence of the cargo and is characterized from the ER after reintroduction of the corresponding gene [27]. Also by seven tetratricopeptide repeats. Pex7 is a WD40 protein which recog- in higher eukaryotes, it is shown that peroxisomal