BBA - Molecular and Cell Biology of Lipids 1862 (2017) 589–599

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BBA - Molecular and Cell Biology of Lipids

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Review Lipid sugar carriers at the extremes: The phosphodolichols Archaea use in N- MARK

⁎ Jerry Eichlera, , Ziqiang Guanb a Department of Life Sciences, Ben Gurion University of the Negev, Beersheva 84105, Israel b Department of Biochemistry, Duke University Medical Center, Durham, NC 27710, USA

ARTICLE INFO ABSTRACT

Keywords: N-glycosylation, a post-translational modification whereby glycans are covalently linked to select Asn residues of Archaea target proteins, occurs in all three domains of life. Across evolution, the N-linked glycans are initially assembled on phosphorylated cytoplasmically-oriented polyisoprenoids, with polyprenol (mainly C55 undecaprenol) Isoprene fulfilling this role in Bacteria and dolichol assuming this function in Eukarya and Archaea. The eukaryal and N-glycosylation archaeal versions of dolichol can, however, be distinguished on the basis of their length, degree of saturation and Oligosaccharyltransferase by other traits. As is true for many facets of their biology, Archaea, best known in their capacity as Prenyltransferase extremophiles, present unique approaches for synthesizing phosphodolichols. At the same time, general insight into the assembly and processing of glycan-bearing phosphodolichols has come from studies of the archaeal responsible. In this review, these and other aspects of archaeal phosphodolichol biology are addressed.

1. Introduction abilities of Archaea to withstand the physical challenges presented by the hostile surroundings that they often inhabit, although how such Life on Earth can be divided into three domains, namely Eukarya, distinctive phospholipid composition would benefit non-extremophilic Bacteria and Archaea [1]. The Archaea, first reported in 1977 [2], were archaea remains unclear [8–10]. For more information on archaeal initially thought of as extremophiles, given their abilities to thrive in phospholipids, the reader is directed to reviews on the topic some of the harshest environments on the planet, including those [6,7,11–13]. characterized by extremes of temperature, pH or salinity. However, it In addition to isoprenoid-based phospholipids and glycolipids, the has since become clear that Archaea are major residents of so-called archaeal plasma membrane also includes isoprenoid-based non-bilayer-

‘normal niches’, such as ocean waters, soil and even intestinal flora forming lipids. These include carotenoids, such as C50 bacterioruberins [3–5]. In terms of their biology, Archaea can be considered a mosaic, and C40 carotenes [14], retinals, such as those associated with presenting traits shared by Eukarya and/or Bacteria, together with bacteriorhodopsin and other sensory and transport rhodopsins [15], elements that distinguish this form of life, such as the unique lipids and phosphodolichols, lipids involved in protein N-glycosylation comprising the archaeal membrane [6]. [16,17]. In the following, current knowledge on the phosphodolichols As in Eukarya and Bacteria, the archaeal cell is also surrounded by a that participate in archaeal N-glycosylation is reviewed. phospholipid-based membrane. Yet, whereas eukaryal and bacterial phospholipids essentially comprise fatty acid side chains linked to a 1,2- 2. The lipid glycan carriers of N-glycosylation across evolution sn-glycerol-3-phosphate backbone via ester bonds, their archaeal counterparts instead correspond to isoprenoid hydrocarbon side chains Long held to be an exclusively eukaryal post-translational modifica- linked to a 2,3-sn-glycerol-1-phosphate backbone via ether bonds [6]. tion, it is now clear that both Bacteria and Archaea can also perform N- While such lipids are organized into the bilayer structure that deline- glycosylation, i.e., the covalent attachment of mono- to polysaccharides ates most archaeal cells, some Archaea are instead surrounded by to select Asn residues of target proteins [18]. Archaea, however, display membranes based on a lipid monolayer comprising tetraether lipids in a degree of diversity in all aspects of N-glycosylation that is unpar- which both ends of the isoprenoid side chains are ether-bound to alleled in either Eukarya or Bacteria [19]. Such diversity is evident at glycerol phosphate backbones [7]. It is thought that the unusual the level of the lipid carrier upon which N-linked glycans are physicochemical properties of their membrane lipids contribute to the assembled.

⁎ Corresponding author at: Dept. of Life Sciences, Ben Gurion University of the Negev, PO Box 653, Beersheva 84105, Israel. E-mail address: [email protected] (J. Eichler). http://dx.doi.org/10.1016/j.bbalip.2017.03.005 Received 26 December 2016; Received in revised form 15 March 2017; Accepted 17 March 2017 Available online 19 March 2017 1388-1981/ © 2017 Elsevier B.V. All rights reserved. J. Eichler, Z. Guan BBA - Molecular and Cell Biology of Lipids 1862 (2017) 589–599

At present, the process of N-glycosylation is best understood in subunits, members of which are found in all organisms [38,39]. While higher Eukarya [20,21]. Here, the sugar N-acetylglucosamine both contain up to 25 isoprene subunits and present a hydroxyl group at (GlcNAc)-1-phosphate, donated by UDP-GlcNAc, is first added to the so-called α end, include a saturated α position isoprene dolichol phosphate (DolP) to yield dolichol pyrophosphate (DolPP)- subunit, whereas polyprenols, including C55 undecaprenol, do not. The bound GlcNAc-1-phosphate. Six additional nucleotide-activated sugars dolichols used in eukaryal N-glycosylation can, however, be distin- are next added to yield heptasaccharide-charged DolPP. This moiety is guished from their archaeal counterparts in that all of the dolichols then flipped across the (ER) membrane to face shown to participate in archaeal N-glycosylation to date also present an the ER lumen by an ATP-independent flippase that remains to be additional saturated isoprene subunit at the ω position, namely that described. At this point, seven more sugars, each delivered from a isoprene farthest from the α end of the molecule distinct DolP carrier charged on the cytoplasmic face of the ER [27,29,32,34,35,37,40,41]. The significance of saturation of the ω membrane and flipped to face the ER lumen, are added to yield a 14- position isoprene is not clear, since in vitro studies revealed how member branched oligosaccharide that is ultimately transferred to C55,60 DolP saturated solely at the α position could be glycan-charged select Asn residues of a nascent polypeptide entering the ER lumen using enzymes involved in N-glycosylation in the methanogen Metha- by the multimeric oligosaccharyltransferase, with Stt3 serving as the nococcus voltae (grown in the laboratory in a 80% H2/20% CO2 catalytic subunit of the complex. atmosphere [42]). Moreover, this glycan-charged lipid could serve as In Bacteria, where N-glycosylation is apparently restricted to only for the archaeal oligosaccharyltransferase AglB. At the same certain groups, the process involved has been best described in the time, in the thermophile Pyrococcus horikoshii (optimal growth at 98 °C pathogen Campylobacter jejuni [22,23]. Here, some 60 different proteins [43]), both undecaprenol phosphate and dolichol phosphate were are modified by a heptasaccharide assembled by a pathway reminiscent reported to serve as substrates for DolP mannose synthase, the of its eukaryal counterpart. In C. jejuni, N-glycosylation begins with the that charges DolP with mannose, raising questions as to the importance generation of di-N-acetylbacillosamine-charged undecaprenol pyropho- of α position isoprene saturation in archaeal N-glycosylation [44]. sphate (UndPP) via the fusion of a UDP-charged version of the sugar with undecaprenol phosphate on the cytoplasmic face of the plasma 3. The diversity of archaeal phosphodolichols membrane. Following glycan extension through the addition of six more sugars, the UndPP-linked heptasaccharide is flipped across the In addition to the saturated ω position isoprene subunit that membrane in a reaction involving the ABC transporter PglK. Once on differentiates archaeal dolichol from the eukaryal version of this lipid, the outer surface of the plasma membrane, the glycan is delivered to the dolichols employed in archaeal N-glycosylation also present various select Asn residues of target proteins by PglB, the bacterial oligosac- species-specific characteristics. These differences are mostly manifested charyltransferase. in terms of dolichol length, degree of phosphorylation and the extent of In Archaea, where the first example of non-eukaryal N-glycosylation internal isoprene subunit saturation (Fig. 2). was reported [24], the process remains the least well understood. In To date, phosphorylated dolichols, many charged with the same part, this is due to the fact that the vast majority of identified strains glycans as N-linked to in the same species, have been cannot be grown in the laboratory, and of the small number of detected in Archaea representing several phenotypes and belonging to cultivatable strains, genetic tools are only available for few. Further- different phyla. The first phosphorylated dolichols detected in Archaea more, the N-linked glycans decorating archaeal glycoproteins demon- were in Hbt. salinarum, soon after this halophile provided the first strate enormous variability in terms of composition and architecture, example of non-eukaryal N-glycosylation, namely the S-layer glycopro- reflecting the variety of N-glycosylation processes employed in Archaea tein [24,45,46]. Here, C55,60 DolP is modified by a sulfated tetra/ [19,25]. Still, what is known reveals that as in the other two domains, pentasaccharide N-linked to ten N-glycosylation sites of the protein,

N-glycosylation in Archaea begins with the assembly of a glycan on one while C55–60 DolPP is modified by a distinct sulfated pentasaccharide or more phosphorylated dolichol carriers. For instance, the first four that apparently assembles into a chain when linked to the Asn-2 sugars of the N-linked pentasaccharide decorating glycoproteins in the position of the protein [31,32,46,47]. It is, however, not known halophile (‘salt-loving’ organism) Haloferax volcanii (optimal growth in whether the chain of repeating sulfated pentasaccharides is assembled 1.5–2.5 M NaCl [26]) are assembled on a common DolP carrier, while on a single DolPP carrier (and if so, on which side of the membrane) the final sugar is delivered from a distinct DolP [27]. As such, DolP and only then transferred to the protein, or alternatively, whether such serves both as lipid glycan carrier and glycan donor in this organism. By polymerization results from the transfer of the subunit glycan to the contrast, the similar N-linked pentasaccharide attached to glycoproteins protein from a series of glycan-charged DolPP carriers assembled on the of a second haloarchaea also originating from the Dead Sea, Haloarcula cytoplasmic face of the membrane and then flipped to face the exterior, marismortui (optimal growth in 3.5–4 M NaCl [28] ), is completely where N-glycosylation transpires [48]. assembled on a single DolP carrier [29]. In yet another halophilic Recently, saturation of the α and ω position isoprenes of Hbt. archaea, Halobacterium salinarum (optimal growth in 3.9 M NaCl [30]), salinarum C55,60 DolP and C55,60 DolPP was demonstrated. In these the surface (S)-layer , the building block of the S-layer studies, DolP was detected bearing a disaccharide precursor of the surrounding the cell, is simultaneously modified by two distinct N- tetra/pentasaccharide, while DolPP was shown to be modified by the linked glycans, one initially assembled on DolP, the second on DolPP first four sugars of the repeating pentasaccharide; DollPP bearing [31,32]. In the thermoacidophile Sulfolobus acidocaldarius (optimal repeats of this glycan was not observed [32]. However, the first growth at 80 °C and pH 2 [33]), DolPP is charged with the same demonstration of dolichol saturation at both ends of the lipid was hexasaccharide as N-linked to glycoproteins in this organism, as well as reported in the case C55,60 DolP bearing a tetrasaccharide in Hfx. its derivatives, although DolP and hexose-charged DolP have also been volcanii [40]. Much later, the tetrasaccharide attached to this DolP was detected [34,35]. In the related species Sulfolobus solfataricus (optimal shown to modify at least one Asn of the S-layer glycoprotein when the growth at 87 °C and pH 3.5–5 [36]), DolPP is charged with the first six cells were grown in 1.7 M NaCl [49], considered as low salinity for this sugars of the heptasaccharide N-linked to glycoproteins in this organ- halophile [26]. Indeed, the most convincing evidence for the involve- ism; the final sugar could thus be derived from hexose-charged DolP ment of DolP in archaeal N-glycosylation has come from studies on Hfx. [37]. As such, it appears that N-glycosylation in Archaea relies on a volcanii, where the deletion of encoding components of the N- variety of lipid-linked glycan processing strategies. glycosylation pathway yielded the same effects on the glycans linked to The dolichols and polyprenols that serve as lipid glycan carriers both DolP and to a target protein, the S-layer glycoprotein [27]. across evolution (Fig. 1; Table 1) are examples of polyisoprenoids, a Subsequently, C55,60 DolP saturated at both the α and ω position family of hydrophobic polymers containing linearly linked isoprene isoprenes was observed in other haloarchaea, namely Har. marismortui,

590 J. Eichler, Z. Guan BBA - Molecular and Cell Biology of Lipids 1862 (2017) 589–599

Fig. 1. Lipid glycan carriers used across evolution.Examples of lipid glycan carriers from Eukarya (human C95 DolPP (trans3cis16 isoprenes) charged with the tetradecasaccharide

GlcNAc2-Man9-Glc3 where Glc is glucose, GlcNAc is N-acetylglucosamine and Man is mannose), Bacteria (C. jejuni C55 UndPP (trans3cis8 isoprenes) charged with the heptasaccharide GalNAc-α1,4-GalNAc-α1,4-[Glc-β-1,3]GalNAc-α1,4-GalNAc-α1,4-GalNAc-α1,3-diNAcBac where diNAcBac is 2,4-diacetamido-2,4,6-trideoxy-D-glucopyranose, GalNAc is N-acetylgalac- tosamine and Glc is glucose) and Archaea (Hfx. volcanii C60 DolP (trans4cis8 isoprenes, predicted) charged with methyl-O-4-GlcA-β-1,4-GalA-α1,4-GlcA-β1,4-glucose where GalA is galacturonic acid and GlcA is glucuronic acid). In each lipid, the arrow depicts the α position isoprene while the arrowhead depicts the ω position isoprene. In the eukaryal and archaeal lipids, the α position isoprene is saturated, whereas the ω position isoprene is saturated only in the archaeal lipid.

Table 1 A comparison of lipid glycan carriers used in N-glycosylation across evolution.

Eukarya Bacteria Archaea

Lipid glycan carrier DolP UndPP DolP DolPP DolPP

Length C70–C105 C50–C60 C30–C70 Positions of saturated isoprenes α-position isoprene None α- and ω-position isoprenes; variable number of internal position isoprenes Location ER membrane Plasma membrane Plasma membrane Topology of sugar addition Sugars added on both sides of the membrane Sugars added only on the cytosolic side of the Sugars added on the cytosolic side of the membrane membrane and in some species, on the external side of the membrane Number of lipid glycan carriers Multiple Single Single or more in some species used per N-glycosylation event Chemical modification of lipid- No No In some species linked glycan Recycling after glycan transfer to DolPP is dephosphorylated to DolP, flipped UndPP is dephosphophorylated to UndP, flipped to Unknown target protein to face the ER lumen and recharged to yield face the cytoplasm and recharged to yield UndPP- DolPP-glycan glycan

591 J. Eichler, Z. Guan BBA - Molecular and Cell Biology of Lipids 1862 (2017) 589–599

Fig. 2. Phosphodolichols used in archaeal N-glycosylation. Archaeal N-glycosylation relies on phosphodolichols that differ in terms of length, degree of phosphorylation and the extent of internal isoprene subunit saturation. Shown are major phosphodolichol species used (or present) in N-glycosylation in different Archaea.

where the lipid was modified by the same pentasaccharide as found on C60,65,70 DolP modified by glycans containing up to the first six sugars the S-layer glycoprotein in this species [29], and Haloferax mediterranei, found in the N-linked heptasaccharide that decorates glycoproteins in where the lipid was modified by a disaccharide [32]. Presently, nothing this organism was described [37,41]. As such, P. furiosus DolP is the else is known about N-glycosylation in Hfx. mediterranei. longest phosphodolichol involved in archaeal N-glycosylation known to Haloarchaea, such as those considered above, belong to the date. More striking, however, was the finding that in addition to being Euryarchaeota, one of the better-studied archaeal phyla [1,50]. The saturated at the α and ω position isoprenes, P. furiosus DolP is also same phylum also includes the methanogens, namely Archaea able to saturated at up to four more internal isoprene positions, with these reduce carbon dioxide with hydrogen to generate methane [51].To additional sites of saturation being closer to the ω than the α end of the date, phosphorylated dolichols have only been characterized in two molecule. In A. fulgidus (optimal growth at 83 °C [58]), C55,60 DolP species. In Methanococcus maripaludis (grown in the laboratory in a 80% displays saturation of not only the α and ω position isoprenes but also

H2/20% CO2 atmosphere [52]), a lipid extract was shown to contain of up to four additional internal isoprene positions [37]. Moreover, A. C55 DolP saturated at two non-specified positions and modified by a fulgidus DolP is apparently modified by two distinct heptasaccharides trisaccharide that corresponds to a precursor of the tetrasaccharide N- [37]. The different lipid-linked glycans could reflect the fact that A. linked to glycoproteins in this organism [53,54]. Moreover, the enzyme fulgidus encodes multiple versions of the oligosaccharyltransferase AglB thought to add the initial sugar to the lipid carrier in M. maripaludis was [59], responsible for the transfer of the glycan moiety from the lipid shown to be more active when presented with C55,60 DolP rather than carrier to select Asn residues of modified proteins (see below), raising with longer C85–105 DolP, as found in eukaryotes [54]. In contrast, older the possibility that different versions of the enzyme process distinct studies conducted on Methanothermus fervidus (optimal growth at 83 °C glycan substrates. in a 80% H2/20% CO2 atmosphere [55]), where the S-layer glycopro- In addition to the phosphodolichols involved in N-glycosylation tein is modified by an N-linked hexasaccharide, detected sugar-mod- studied in representatives of the Euryarchaeota, these lipids have also ified C55 DolPP [56]. been considered in three members of a second well-studied archaeal In addition to halophiles and methanogens, the Euryarchaeota also phylum, the Crenarchaeota [1,50]. S. acidocaldarius is the only cre- include thermophilic archaea where phosphodolichols involved in N- narchaeote for which insight into the N-glycosylation process is glycosylation have been characterized, namely Pyrococcus furiosus and available. Here, C40,45,50 DolP, in some cases charged with one of three Archaeoglobus fulgidus.InP. furiosus (optimal growth at 100 °C [57]), different hexoses, and C45 DolPP modified by the hexasaccharide added

592 J. Eichler, Z. Guan BBA - Molecular and Cell Biology of Lipids 1862 (2017) 589–599 to target proteins in N-glycosylation, as well as by glycans comprising mevalonate pyrophosphate decarboxylase to generate IPP, which is the first four of five sugars of this structure, were detected [34,35].InS. isomerized by IPP to yield DMAPP (Fig. 3). acidocaldarius DolP and DolPP, up to six isoprenes are saturated, Genomic analyses revealed the presence of the first four enzymes of including those at the α and ω positions. In the related thermoacido- the classic mevalonate pathway in Archaea, namely acetoacetyl-CoA phile S. solfataricus,C30 and C45 DolPP modified by the first six sugars of thiolase, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) the N-linked heptasaccharide assembled in this species [60] and synthase, HMG-CoA reductase and mevalonate-5- [65,66]. Sub- saturated at the α and ω isoprene positions, as well as at up to four sequent efforts not only confirmed the functionality of archaeal additional internal position isoprenes, were identified [37]. Moreover, versions of these enzymes but also revealed unique properties in several it has been suggested that the two phosphodolichol glycan carriers used instances. For example, Hfx. volcanii HMG-CoA reductase is regulated at in S. solfataricus N-glycosylation differ not only in length (C30 and C45) the transcription level by environmental salinity, pointing to a link but also in terms of stereochemistry [37]. At the same time, Pyrobacu- between the cell surroundings and the biosynthesis of isoprenoids, lum calidifontis (optimal growth at 90–95 °C [61]) was reported to including phosphodolichols [67]. Moreover, Hfx. volcanii HMG-CoA contain C50,55 DolPP modified by a decasaccharide also shown to be N- reductase is the first such enzyme that is not sensitive to feedback linked to a glycopeptide generated by proteolytic digestion of a inhibition by its substrate, acetoacetyl-CoA [68]. Likewise, known membrane fraction prepared from this organism [37]. Similarly to the feedback inhibitors of mevalonate-5- do not inhibit the Metha- phosphodolichols in other crenarchaeotes considered to date, P. nosarcina mazei enzyme, making it the sole member of a third class of calidifontis DolPP is saturated at the α position isoprene, at up to five mevalonate kinases defined on the basis of inhibition profile [69]. internal position isoprenes and at the ω position isoprene [37]. At the same time, genomic scanning failed to detect archaeal Despite the limited number of archaeal species in which phospho- homologues of mevalonate pyrophosphate decarboxylase in most dolichols either shown or likely to be involved in N-glycosylation have species [65,66,70], suggesting the existence of an alternate route for been characterized, general considerations on the use of these lipids the conversion of mevalonate-5-phosphate to IPP. Initial support for may have already been revealed. With the exception of M. fervidus, this hypothesis came with the identification of an isopentenyl phos- where older technologies were employed, it would appear that N- phate kinase in Methanocaldococcus jannaschii (optimal growth at 85 °C glycosylation in the Euryarchaeota relies on DolP as glycan lipid in a 80% H2/20% CO2 atmosphere; first isolated from a hydrothermal carrier, with the N-linked glycan either being assembled on a single vent on the Pacific Ocean floor [71]), namely an enzyme that DolP carrier or alternatively, being assembled on the modified protein synthesizes IPP via the phosphorylation of isopentenyl phosphate from precursors delivered from at least two DolP carriers. In contrast, [72]. Genomic analyses revealed that other Archaea also contain the Crenarchaeota rely on DolPP as lipid glycan carrier, with DolP possibly encoding this protein, with the activity of recombinant isopente- serving as the carrier of individual sugars either delivered to DolPP- nyl phosphate kinase from Methanothermobacter themautotrophicus linked precursors of N-linked glycans or to glycans already transferred (optimal growth at 65–70 °C in a 80% H2/20% CO2 atmosphere [73]) from DolPP carriers to target protein Asn residues. As such, it would and Thermoplasma acidophilum (optimal growth at 59 °C and pH 1–2 appear that euryarchaeotes rely on a more bacterial-like N-glycosyla- [74]) having been demonstrated [75]. Subsequent efforts uncovered the tion process, whereas crenarchaeotes rely on a process reminiscent of existence of both phosphomevalonate decarboxylase, responsible for that employed in Eukarya. Indeed, phylogenetic analyses of known converting mevalonate-5-phosphate into isopentenyl phosphate, and Archaea position the Crenarchaeota proximal to the ancestor of isopentenyl phosphate kinase in Hfx. volcanii, thereby confirmed the modern-day eukaryotes [62,63]. existence of an alternate route for IPP biosynthesis in Archaea (Fig. 3) In addition, the fact that DolP and DolPP from both thermophilic [76]. Nonetheless, there are archaeal species that rely on the classic euryarchaeotes and crenarchaeotes include saturated isoprenes at mevalonate pathway despite also encoding components of the alternate internal positions points to dolichol isoprene reduction as being pathway, such as S. solfataricus [77]. Here too, Archaea have introduced important for survival at high temperatures. Such enhanced saturation, unusual variations not seen elsewhere. For instance, while the meva- relative to what is seen in mesophilic archaea, would reduce the lonate pyrophosphate decarboxylase in S. solfataricus exists as a dimer, movement of phosphodolichols in the membranes of thermophilic like its eukaryal and bacterial counterparts, the archaeal enzyme is archaea, a property that could be important for the enzyme-mediated unique in that a disulfide bond serves to stabilize the dimer in this processing of these glycan carriers. At the same time, dolichol length thermoacidophile [78]. Recently, evidence for the existence of yet does not seem to be sensitive to temperature, since both the shortest another pathway for IPP biosynthesis in Archaea has been presented. In

(C30) and longest (C70) archaeal phosphodolichols known to date have T. acidophilum, mevalonate-3-kinase converts mevalonate into mevalo- been detected in thermophiles [37,41]. nate-3-phosphate, which is then converted into mevalonate-3,5-bispho- sphate by mevalonate-3-phosphate-5-kinase [79,80]. Mevolonate-3- 4. Phosphodolichol biosynthesis in Archaea kinase was subsequently described in Picrophilus torridus (optimal growth at 60 °C and pH 1.8–2 [81]), with sequence analysis suggesting Phosphodolichol synthesis occurs in two stages [38,39]. In the first the enzyme to also exist in other members of the Thermoplasmatales, the stage, the two building blocks of isoprenoid biogenesis, isopentenyl order that includes these two species [82]. Presently, however, the pyrophosphate (IPP) and its isomer dimethylallyldiphosphate mevalonate-3,5-bisphosphate decarboxylase that would be required for (DMAPP), are generated from acetyl CoA. This is followed by the the appearance of IPP by this novel route has yet to be identified second stage of dolichol biogenesis in which a series of condensation (Fig. 3). Finally, the IPP used by Archaea to convert IPP into reactions between DMAPP and several IPP moieties occurs. The DMAPP are, for the most part, orthologs of a bacterial, rather than the resulting polymer is then further processed to yield the phosphorylated eukaryal version of this enzyme [83]. This, despite the fact that many dolichols used in archaeal N-glycosylation. Bacteria do not use the MVA pathway but rather rely on a distinct The classic route for generating IPP and DMAPP is known as the pathway for IPP biosynthesis termed the MEP/DOXP pathway, as do mevalonate pathway [64]. Here, three acetyl CoA molecules are plants [84,85]. Members of the archaeal order Halobacteriales, however, condensed and reduced using NADPH to yield mevalonate via the encode both versions of the isomerase [66]. sequential actions of acetoacetyl-CoA thiolase, 3-hydroxy-3-methylglu- To generate phosphodolichols from the five-carbon precursors IPP taryl (HMG)-CoA synthase and HMG-CoA reductase. Mevalonate is and DMAPP, there is a need for elongation steps in which DMAPP and subsequently phosphorylated by mevalonate-5-kinase and phosphome- multiple IPP moieties polymerize to yield an isoprenoid chain, depho- valonate kinase to yield mevalonate-5-phosphate and mevalonate sphorylation steps to yield a polyprenol, saturation steps to reduce the pyrophosphate, respectively. The latter compound is processed by isoprene subunit at the α end of the dolichol molecule (and, in Archaea,

593 J. Eichler, Z. Guan BBA - Molecular and Cell Biology of Lipids 1862 (2017) 589–599

Fig. 3. Pathways of isopentenyl pyrophosphate biosynthesis in Archaea. In Archaea, isopentenyl pyrophosphate can be synthesized by different pathways. In the classic mevalonate pathway, mevalonate undergoes two rounds of phosphorylation at the 5 position and then decarboxylation at the 3 position to yield IPP. In a second pathway, mevalonate undergoes phosphorylation at the 5 position, decarboxylation at the 3 position and then a second phosphorylation at the 5 position to generate IPP. In a potentially third pathway, mevalonate is phosphorylated at the 3 position and then at the 5 position. Dephosphorylation at the 3 position, a reaction yet to be observed, would yield isopentenyl phosphate, which would be phosphorylated at the 5 position to produce IPP. the isoprene subunit at the ω position, and in some cases, at more Now found within the membrane, the polyprenol pyrophosphate is internal positions) and finally, phosphorylation steps. While the details next thought to undergo two rounds of dephosphorylation to yield of many of these reactions are relatively well described in Eukarya (and polyprenol [87,88]. In Eukarya, saturation of the α position isoprene in undecaprenol synthesis in Bacteria, where saturation steps are not subunit is proposed to occur at this stage, yielding dolichol; in Bacteria, required), much less is known about the route(s) taken in Archaea. no such saturation occurs. Finally, dolichol is phosphorylated by Polyprenol biosynthesis begins with DMAPP serving as the acceptor dolichol kinase to generate DolP [87,89]. In Bacteria, an undecaprenol for an IPP molecule to generate C10 geranyl pyrophosphate [38,39]. phosphokinase that catalyzes a similar reaction has been described This reaction, as well as the addition of a second IPP to generate C15 [38,90]. Whereas there is considerable understanding of the steps taken farnesyl pyrophosphate, involves trans-condensations catalyzed by to synthesize IPP and DMAPP in Archaea, insight into how Archaea isoprenyl pyrophosphate synthases, also termed prenyltransferases, assemble phosphodolichol from these building blocks remains only members of an enzyme family responsible for generating polyprenol partial. Nonetheless, what is currently known has revealed unexpected chains of increasing length [86]. Following the condensation of IPP aspects of each of the latter steps of phosphodolichol assembly, namely moieties in trans, additional IPP units are added in cis by a cis- elongation, dephosphorylation, saturation and phosphorylation. prenyltransferase to generate a trans/cis-polyprenol pyrophosphate. The sequential addition of IPP subunits to a DMAPP acceptor is

594 J. Eichler, Z. Guan BBA - Molecular and Cell Biology of Lipids 1862 (2017) 589–599 catalyzed by distinct prenyltransferases that catalyze condensation tion, saturation and then phosphorylation to generate DolP. reactions as a function of substrate length [86]. To generate dolichol, The conversion of polyprenol pyrophosphates to polyprenol re- the so-called short-chain prenyltransferases are required [91]. In most quires dephosphorylation. In Eukarya, the enzyme(s) responsible has

Archaea, the only members of this group are C20 geranylgeranyl (have) yet to be described, although polyprenol pyrophosphate phos- pyrophosphate synthases [92,93]. These, however, can assemble phatase and polyprenol phosphatase activities have been observed in trans-polyprenol pyrophosphates of different lengths, as exemplified whole-cell homogenates [113]. In Bacteria, undecaprenol pyropho- by the bi-functional enzyme from M. themautotrophicus that is able to sphate is converted to undecaprenol phosphate by the actions of UppP synthesize both farnesyl pyrophosphate and geranylgeranyl pyropho- [114]. The resulting mono-phosphorylated polymer serves as the sphate [94]. Similar bi-functional activity was reported for geranylger- bacterial lipid glycan carrier. In Archaea, it is assumed that depho- anyl pyrophosphate synthases from S. acidocaldarius and Thermococcus sphorylation also occurs. Indeed, undecaprenol (and dolichol) has been kodakarensis (optimal growth at 95 °C [95]) [96,97]. Based on such observed in M. acetivorans [115]. Likewise, the detection of dolichol in observations, it has been proposed that archaeal geranylgeranyl S. acidocaldarius [34] could reflect the initial dephosphorylation of pyrophosphate synthases represent the ancestor of the farnesyl pyr- polyprenol pyrophosphates, although here too, the enzyme(s) respon- ophosphate synthases and geranylgeranyl pyrophosphate synthases sible remain(s) to be identified. Finally, while roles for polyprenol and presently found in Eukarya and Bacteria [98,99]. This hypothesis has, dolichol have been proposed in Bacteria and Eukarya, respectively however, been questioned by others [100]. Finally, in S. acidocaldarius, [17], it is not known whether dolichol serves any biological function in genes encoding IPP isomerase (saci0091), geranylgeranyl pyropho- Archaea. sphate synthase (saci0092) and AglH, the glycosyltransferase respon- In the presumed next step in phosphodolichol biosynthesis, satura- sible for adding the first sugar of the N-linked glycan to DolPP tion of the isoprene subunit found at the α position of polyprenol is (saci0093), lay adjacent to each other in the genome, with saci0092 thought to occur. In Archaea, saturation of the isoprene subunit at the ω and saci0093 being found on the same polycistronic mRNA [101,102]. position would likely also occur at this point, as would the saturation of This gene arrangement offers support for close interplay between other isoprene subunits found at more internal positions in those in phosphodolichol biosynthesis and N-glycosylation in this thermoacido- species where highly saturated phosphodolichols exist. A polyprenol phile. reductase responsible for saturation of the α position isoprene subunit In general, the substrate (or primer) of cis-prenyltransferases in of polyprenol has been identified in Eukarya [116]. The enzyme,

Eukarya and Bacteria is C15 trans-farnesyl pyrophosphate [38,39,91], encoded by the SRD5A3 gene in humans, has no archaeal homologue. although evidence for the broader selectively of these enzymes in plants As such, it would appear that Archaea rely on a distinct enzyme for such has been offered [103,104]. In Archaea, both C15 trans-farnesyl activity. Furthermore, given that eukaryal cells lacking SRD5A3 can pyrophosphate and C20 trans-geranylgeranyl pyrophosphate serve as still generate some 30% of the dolichol found in normal cells [116],it cis-prenyltransferase substrates [92].InS. acidocaldarius, apparently would seem that at least one more eukaryal polyprenol reductase must only trans-geranylgeranyl pyrophosphate serves this role [92]. The exist. One can speculate that Archaea, lacking a SRD5A3 gene, could recent report of one of the three cis-prenyltransferases in Methanosarci- instead contain homologues of this(these) additional polyprenol re- na acetivorans being able to catalyze both head-to-tail and non-head-to- ductase(s), considering the high number of saturated isoprenes in tail condensation reactions [105] could reflect yet another unique archaeal phosphodolichols. To date, archaeal proteins showing poly- aspect of archaeal phosphodolichol biosynthesis. In the hyperthermo- prenol reductase activity have been described. S. acidocaldarius con- phile Aeropyrum pernix (optimal growth at 90–95 °C [106]), the cis- tains a geranylgeranyl reductase that is able to saturate three of the four 2 prenyltransferase is unusual in that the substrate is C25 trans-geranyl- double bonds in geranylgeranyl pyrophosphate, leaving the Δ double farnesyl pyrophosphate [107]. This could indicate the use of a unique bond intact and thereby yielding a substrate for prenyltransferases in a lipid glycan carrier in this species. Accordingly, it is of note that when reaction that would result in the removal of the pyrophosphate group 168 archaeal genomes were considered for the presence of aglB, from the geranylgeranyl pyrophosphate substrate [117]. Recent crystal- encoding the archaeal oligosaccharyltransferase responsible for the lographic analysis of S. acidocaldarius geranylgeranyl reductase bound transfer of glycans from phosphodolichol carriers to target protein to geranylgeranyl pyrophosphate has provided insight into the catalytic Asn residues, A. pernix was only one of two species where no such gene mechanism of this enzyme [118]. In contrast to the geranylgeranyl was detected, raising the question of whether N-glycosylation occurs in reductase of T. acidophilum, which uses NADPH as electron donor this organism [108]. However, if N-glycosylation indeed occurs in A. [119], the S. acidocaldarius enzyme does not use either NADPH or pernix, the process may rely on an oligosaccharyltransferase distinct NADH, and as such, the source of electrons used in the saturation from AglB. Lastly, it has been reported that in mammalian cells, cis- reaction in this species is not known [117]. In the case of M. acetivorans prenyltransferases require interaction with the NogoB receptor for geranylgeranyl reductase, ferrodoxin is thought to serve as electron stabilization of the enzyme [109]. In plants, where cis-prenyltrans- donor [120]. In addition, reductases that saturate the ω position ferases exist as enzyme families, it was shown that select family isoprene subunit of polyprenol, all members of the geranylgeranyl members that contribute to dolichol biogenesis also interact with a reductase family, have also been identified. These enzymes, however, NogoB receptor homologue [103,110]. Although phylogenetic analysis affect the saturation status of other lipids as well, raising the question of has raised the possibility of such a protein in Archaea [105], evidence whether these reductases are truly components of the phopshodolichol for the involvement of a NogoB receptor homologue in archaeal cis- biosynthesis pathway in Archaea [115,121]. Indeed, the observation prenyltransferase activity has yet to be presented. that S. acidocaldarius contains versions of C45 DolP presenting satura- Once the polyprenol pyrophosphates destined to become phospho- tion at the α position isoprene subunit, at the α and ω position isoprene dolichols have been assembled, it is believed that they must next subunits and at these two positions together as well as at one-four more undergo dephosphorylation, saturation and phosphorylation [111], internal positions, suggests that multiple reductases contribute to although conclusive evidence that this is indeed the order of events phosphodolichol biosynthesis here [34]. Finally, considering that two in Archaea remains wanting. With this in mind, a scheme of the possible or more of the isoprene subunits comprising archaeal dolichols are steps taken during the latter phase of archaeal DolP biosynthesis, using saturated, it has been proposed that archaeal dolichols should be called S. acidocaldarius as a model system [34], is presented in Fig. 4. Indeed, archaeoprenols, so as to distinguish them from their less saturated it should be noted that alternate pathways leading to the appearance of eukaryal counterparts [122]. DolP exist in other forms of life [112], and, therefore, possibly in In what is assumed to be the final step of DolP biosynthesis, dolichol Archaea as well. Nonetheless, in this review it is assumed that in is phosphorylated. In Eukarya, this reaction is catalyzed by a CTP- Archaea, polyprenol pyrophosphates are subjected to dephosphoryla- dependent dolichol kinase [123,124]. Homology-based searches of

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Fig. 4. Potential pathways for the biosynthesis of DolP in Archaea. The biogenesis of DolP in S. acidocaldarius offers an example of the potential pathways used for synthesizing phosphodolichols in Archaea. Initially (not shown), three isopentenyl pyrophosphates and dimethylallyldiphosphate combine to form geranylgeranyl pyrophosphate (GGPP). Where internal phosphodolichol isoprenes are reduced, as in S. acidocaldarius, three of the four double bonds in GGPP may be reduced at this stage; the α position isoprene remains unsaturated. Elongation occurs when additional isoprene subunits (four-six in the case of S. acidocaldarius) are added to the α end of GGPP to generate polyprenol pyrophosphate. The generation of dolichol requires the removal of the two phosphate groups, followed by reduction of the α position isoprene subunit (and possibly other subunits elsewhere, as in the case of S. acidocaldarius phosphodolichols; when the position of a double bond is only speculated in a S. acidocaldarius lipid in the figure, a dotted line appears). Dolichol would undergo phosphorylation to yield dolichol phosphate (DolP). Alternatively, polyprenol pyrophosphate could undergo reduction reactions, followed by removal of one phosphate group to yield DolP or both phosphate groups, followed by re-phosphorylation, again yielding DolP, as thought to occur in Eukarya. Abbreviations used: DolP, dolichol phosphate; DolPP, dolichol pyrophosphate; GGPP, geranylgeranyl pyrophosphate. archaeal genomes have identified homologues of eukaryal dolichol 5. Phosphodolichol-processing enzymes that participate in kinase in only a limited number of species, implying that dolichol archaeal N-glycosylation phosphorylation in Archaea relies on a distinct enzyme. Once the lipid-linked glycan has been transferred by the oligosac- In terms of both glycan composition and glycan architecture, charyltransferase to a target protein, the lipid carrier can be recycled archaeal N-glycosylation presents a degree of diversity not seen in for subsequent rounds of glycan-charging. In Eukarya, for example, the either Eukarya or Bacteria [19]. Fittingly, what is known of archaeal N- DolPP that remains following N-glycosylation undergoes dephosphor- glycosylation pathways reveals the involvement of numerous species- ylation to yield DolP, which is subsequently returned to the cytoplasmic specific components [25]. In contrast, the oligosaccharyltransferase leaflet of ER, where it is again recruited as a glycan carrier [125,126]. AglB is highly conserved across Archaea. Indeed, like PglB, the bacterial In Archaea, incubation of glycan-charged DolPP from S. solfataricus or oligosaccharyltransferase, and Stt3, the catalytic subunit of the eu- P. calidifontis with a membrane fraction containing the oligosaccharyl- karyal oligosaccharyltransferase, AglB also contains the WWDXG and AglB and an peptide that contained an Asn residue suitable other motifs important for activity. AglB, moreover, presents a topology for glycosylation resulted in the appearance of DolP, suggesting that a similar to those of PglB and Stt3 [131,132]. Solution of the crystal dephosphorylation reaction, similar to that which occurs in Eukarya, structures of the complete AglB protein from A. fulgidus, as well as of also transpires in Archaea where DolPP serves as the lipid glycan carrier the catalytic domain from P. furiosus and those of the three A. fulgidus [37]. Indeed, externally oriented pyrophosphatases from S. acidocaldar- AglB paralogs by the Kohda group [131,133–135] has not only ius and Sulfolobus tokodaii (optimal growth at 80 °C and pH 2.5–3 provided insight into how AglB catalyzes the glycosylation of target [127]) have been described and proposed to participate in DolPP Asn residues but also into how the enzyme interacts with the glycan- recycling [128–130]. bearing phosphodolichol carrier. Analysis of the electron density map of full-length A. fulgidus AglB revealed substantial electron density, modeled as a sulfate ion, 5 Å from the zinc ion found in the catalytic site of the enzyme (that, during the crystallization process, had apparently

596 J. Eichler, Z. Guan BBA - Molecular and Cell Biology of Lipids 1862 (2017) 589–599 replaced the magnesium ion normally associated with the enzyme) Acknowledgements [135]. This sulfate group interacted with His-81, His-162, Trp-215 and Arg-246, residues that are conserved in other AglB sequences. Site- J.E. was supported by grants from the Israel Science Foundation directed mutagenesis showed the importance of the positive charges of (ISF) (grant 109/16), the ISF within the ISF-UGC joint research program His-81, His-162 and Arg-246. Based on these observations, it was framework (grant 2253/15), the ISF-NSFC joint research program assumed that the sulfate ion mimicked the phosphate group of the DolP (grant 2193/16) and the German-Israeli Foundation for Scientific that serves as the glycan lipid carrier in A. fulgidus N-glycosylation [37]. Research and Development (grant I-1290-416.13/2015). Z.G. was Accordingly, a docking model showed a good fit of the DolP dolichol supported by the LIPID MAPS Large Scale Collaborative Grant (GM- chain within the hydrophobic groove on the protein surface leading to 069338) and grant EY023666 from NIH. these residues. Once a crystal structure of AglB from an archaeal species that relies on DolPP as glycan lipid carrier becomes available, it will be References of interest to see if the same architecture applies. Flippases, catalyzing the translocation of glycan-charged and gly- [1] C.R. Woese, O. Kandler, M.L. Wheelis, Towards a natural system of organisms: can-free phosphodolichols across the membrane [136], are also com- proposal for the domains Archaea, Bacteria, and Eucarya, Proc. Natl. Acad. Sci. U. S. A. 87 (1990) 4576–4579. ponents of N-glycosylation pathways in intimate contact with DolP [2] C.R. Woese, G.E. Fox, Phylogenetic structure of the prokaryotic domain: the and/or DolPP. 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