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The Multiple Evolutionary Origins of the Eukaryotic N-Glycosylation Pathway Jonathan Lombard1,2

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The Multiple Evolutionary Origins of the Eukaryotic N-Glycosylation Pathway Jonathan Lombard1,2 Lombard Biology Direct (2016) 11:36 DOI 10.1186/s13062-016-0137-2 RESEARCH Open Access The multiple evolutionary origins of the eukaryotic N-glycosylation pathway Jonathan Lombard1,2 Abstract Background: The N-glycosylation is an essential protein modification taking place in the membranes of the endoplasmic reticulum (ER) in eukaryotes and the plasma membranes in archaea. It shares mechanistic similarities based on the use of polyisoprenol lipid carriers with other glycosylation pathways involved in the synthesis of bacterial cell wall components (e.g. peptidoglycan and teichoic acids). Here, a phylogenomic analysis was carried out to examine the validity of rival hypotheses suggesting alternative archaeal or bacterial origins to the eukaryotic N-glycosylation pathway. Results: The comparison of several polyisoprenol-based glycosylation pathways from the three domains of life shows that most of the implicated proteins belong to a limited number of superfamilies. The N-glycosylation pathway enzymes are ancestral to the eukaryotes, but their origins are mixed: Alg7, Dpm and maybe also one gene of the glycosyltransferase 1 (GT1) superfamily and Stt3 have proteoarchaeal (TACK superphylum) origins; alg2/alg11 may have resulted from the duplication of the original GT1 gene; the lumen glycosyltransferases were probably co-opted and multiplied through several gene duplications during eukaryogenesis; Alg13/Alg14 are more similar to their bacterial homologues; and Alg1, Alg5 and a putative flippase have unknown origins. Conclusions: The origin of the eukaryotic N-glycosylation pathway is not unique and less straightforward than previously thought: some basic components likely have proteoarchaeal origins, but the pathway was extensively developed before the eukaryotic diversification through multiple gene duplications, protein co-options, neofunctionalizations and even possible horizontal gene transfers from bacteria. These results may have important implications for our understanding of the ER evolution and eukaryogenesis. Reviewers: This article was reviewed by Pr. Patrick Forterre and Dr. Sergei Mekhedov (nominated by Editorial Board member Michael Galperin). Keywords: N-glycosylation, Eukaryotes, Archaea, Bacteria, Eukaryogenesis, Prokaryotic cell walls, Polyisoprenol, Glycosyltransferase Background contributor to eukaryogenesis, for at least the mitochondria At the dawn of eukaryotes are known to have evolved from an alpha-proteobacterium All living organisms are traditionally classified into one that was engulfed prior to the last eukaryotic common of three domains of life, namely bacteria, archaea and ancestor (LECA) [1, 2]. The traditional three-domain tree eukaryotes. Eukaryotic cells have important cytological of life posits that eukaryotes and archaea are sister groups specificities, such as nuclei, organelles and other cellular [3–5] and, thus, it assumes that the mitochondrial ances- processes. As a result, the origin of eukaryotes from tor was incorporated in a pre-existing proto-eukaryotic former organisms is one of the most intriguing questions lineage [6, 7]. Other phylogenetic studies have suggested in biology. Endosymbiosis was certainly an important that the eukaryotic stem branched within the archaeal domain, close to the crenarchaea–“eocytes”–or to the Correspondence: [email protected] archaeal TACK superphylum [8–11]. Also, comparative 1 National Evolutionary Synthesis Center, 2024 W. Main Street Suite A200, genomics have shown that many eukaryotic operational Durham, NC 27705, USA 2Biosciences, University of Exeter, Geoffrey Pope Building, Stocker Road, (metabolic) genes are closely related to bacterial Exeter EX4 4QD, UK © 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Lombard Biology Direct (2016) 11:36 Page 2 of 31 homologues, while informational genes are more similar [42]. Archaeal glycans are also more diverse than their to archaeal ones [12]. These observations popularized the eukaryotic equivalents [40]. opinion according to which the eukaryotes are a chimeric N-glycosylation is less common in bacteria, where two lineage that resulted from the endosymbiosis of the N-glycosylation systems are known [43]. One of them bacterial ancestor of mitochondria within a bona fide independently tethers single monosaccharides to specific archaeon [13, 14] or a previous bacterium/archaeon con- amino acids using soluble cytoplasmic proteins. The sortium [15–17]. The recent accumulation of genomic other relies on a lipid-carrier-based mechanism similar data has now made possible to address these issues. The to the eukaryotic and archaeal pathways (Fig. 1b). debate remains open [18–20], but most authors now favor The latter is thought to be restricted to delta- and an archaeal origin of the eukaryotic stem [21–24]. epsilon-proteobacteria [43, 44]. The bacterial polypre- Following the success of comparative analyses to trace nol lipid carriers are unsaturated and have different back particular machineries to LECA [25–32], the origin names depending on their lengths [45]. For simplicity, and evolution of the eukaryotic N-glycosylation pathway they will all be referred to as bactoprenol phosphate will be studied here. (Bac-P). N-glycosylation in the three domains of life The evolution of polyisoprenol-based N-glycosylations More than half of all eukaryotic proteins are glycopro- Since polyisoprenol-based N-glycosylation pathways are teins, and 90 % of those are N-glycosylated [33]. Protein widespread in archaea and eukaryotes but uncommon in N-glycosylation modulates protein stability, solubility, bacteria, it has been speculated that this pathway origi- rigidity, orientation, interactivity, transport and signaling nated in archaea, was horizontally transferred to some [34]. It consists of the covalent attachment of an oligo- bacteria [46, 47] and inherited in eukaryotes from their saccharide to the nitrogen atom of specific asparagine putative archaeal-related progenitor [34, 48]. The poten- residues. In eukaryotes, the synthesis of the oligosac- tial archaeal origin of eukaryotic N-glycosylation recently charide core is mediated by a lipid carrier called brought this pathway into the spotlight of eukary- dolichol-phosphate (Dol-P) which is located in the ogenesis debates [14]. For instance, the “inside-out membranes of the endoplasmic reticulum (ER, Fig. 1a). hypothesis” recently suggested that the eukaryotic In opisthokonts (e.g. in humans and yeast), several nucleus evolved from ancestral “eocytes” (crenarchaeota) cytoplasmic-facing membrane-embedded glycosyltrans- that protruded membrane-bound blebs beyond their cell ferases (GTs) sequentially add monosaccharides from walls to increase the available exchange surface with the soluble nucleotide carriers to Dol-P molecules (Fig. 1b). bacterial ancestors of mitochondria. According to this The Dol-P-oligosaccharide is then “flipped” across the hypothesis, the location of the N-glycosylation pathway membrane and other membrane-embedded GTs resume in the eukaryotic ER membranes is a vestige of the the oligosaccharide decoration in the lumen side. The ancestral archaeal S-layer protein N-glycosylation [14]. monosaccharides used in the ER lumen are also attached The idea that eukaryotic N-glycosylation originated to Dol-P carriers. The final oligosaccharide is transferred from archaea is plausible, but alternative hypotheses en bloc to the acceptor protein located in the ER lumen have also been suggested. For instance, the eukaryotic by a N-oligosaccharyltransferase (N-OST). Soluble GTs N-glycosylation has been thought to be related to some located in the ER and Golgi lumen may subsequently kind of bacterial cell wall synthesis pathway [49–51]. modify the protein N-glycans [35], but these later modi- Indeed, bacterial O-glycosylation, tyrosine O-glycosylation, fications will not be studied in the present analysis. peptidoglycan synthesis, O-antigen LPS synthesis, teichoic In archaea, flagellins and cell wall S-layer proteins are acid synthesis, exopolysaccharide synthesis and, in a N-glycosylated using similar pathways located in their smaller scale, O- and C-mannosylation, use polyisoprenol cell membranes [36, 37]. Archaeal N-glycosylation lipid lipid carriers and a similar orientation across the carriers are traditionally called Dol-P, even though they membrane to protein N-glycosylation. Other observations, are more saturated than the eukaryotic ones (Fig. 1a, without being conclusive, call into question a simple [38–41]). Archaeal N-glycosylation pathways have a transposition of the archaeal N-glycosylation into eukary- topology similar to their eukaryotic counterparts, i.e. the otes: i) archaeal and eukaryotic Dol-P are different orientation of their reactions across the membrane is the molecules (Fig. 1a) [38–41] and they are probably same: archaeal N-glycans are synthesized in the cytoplas- synthesized using different biosynthesis pathways (data to mic face, then flipped to the outer side of cell mem- be published
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