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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-glycosylation

Jerry Eichlera,⁎, Ziqiang Guanb

a Department of Life Sciences, Ben Gurion University of the Negev, Beersheva 84105, Israelb Department of Biochemistry, Duke University Medical Center, Durham, NC 27710, USA

A R T I C L E I N F O

Keywords:ArchaeaDolicholIsopreneN-glycosylationOligosaccharyltransferasePrenyltransferase

A B S T R A C T

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

1. Introduction

Life on Earth can be divided into three domains, namely Eukarya,Bacteria and Archaea [1]. The Archaea, first reported in 1977 [2], wereinitially thought of as extremophiles, given their abilities to thrive insome of the harshest environments on the planet, including thosecharacterized by extremes of temperature, pH or salinity. However, ithas since become clear that Archaea are major residents of so-called‘normal niches’, such as ocean waters, soil and even intestinal flora[3–5]. In terms of their biology, Archaea can be considered a mosaic,presenting traits shared by Eukarya and/or Bacteria, together withelements that distinguish this form of life, such as the unique lipidscomprising the archaeal membrane [6].

As in Eukarya and Bacteria, the archaeal cell is also surrounded by aphospholipid-based membrane. Yet, whereas eukaryal and bacterialphospholipids essentially comprise fatty acid side chains linked to a 1,2-sn-glycerol-3-phosphate backbone via ester bonds, their archaealcounterparts instead correspond to isoprenoid hydrocarbon side chainslinked to a 2,3-sn-glycerol-1-phosphate backbone via ether bonds [6].While such lipids are organized into the bilayer structure that deline-ates most archaeal cells, some Archaea are instead surrounded bymembranes based on a lipid monolayer comprising tetraether lipids inwhich both ends of the isoprenoid side chains are ether-bound toglycerol phosphate backbones [7]. It is thought that the unusualphysicochemical properties of their membrane lipids contribute to the

abilities of Archaea to withstand the physical challenges presented bythe hostile surroundings that they often inhabit, although how suchdistinctive phospholipid composition would benefit non-extremophilicarchaea remains unclear [8–10]. For more information on archaealphospholipids, the reader is directed to reviews on the topic[6,7,11–13].

In addition to isoprenoid-based phospholipids and glycolipids, thearchaeal plasma membrane also includes isoprenoid-based non-bilayer-forming lipids. These include carotenoids, such as C50 bacterioruberinsand C40 carotenes [14], retinals, such as those associated withbacteriorhodopsin and other sensory and transport rhodopsins [15],and phosphodolichols, lipids involved in protein N-glycosylation[16,17]. In the following, current knowledge on the phosphodolicholsthat participate in archaeal N-glycosylation is reviewed.

2. The lipid glycan carriers of N-glycosylation across evolution

Long held to be an exclusively eukaryal post-translational modifica-tion, it is now clear that both Bacteria and Archaea can also perform N-glycosylation, i.e., the covalent attachment of mono- to polysaccharidesto select Asn residues of target proteins [18]. Archaea, however, displaya degree of diversity in all aspects of N-glycosylation that is unpar-alleled in either Eukarya or Bacteria [19]. Such diversity is evident atthe level of the lipid carrier upon which N-linked glycans areassembled.

http://dx.doi.org/10.1016/j.bbalip.2017.03.005Received 26 December 2016; Received in revised form 15 March 2017; Accepted 17 March 2017

⁎ Corresponding author at: Dept. of Life Sciences, Ben Gurion University of the Negev, PO Box 653, Beersheva 84105, Israel.E-mail address: jeichler@bgu.ac.il (J. Eichler).

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

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MARK

At present, the process of N-glycosylation is best understood inhigher Eukarya [20,21]. Here, the sugar N-acetylglucosamine(GlcNAc)-1-phosphate, donated by UDP-GlcNAc, is first added todolichol phosphate (DolP) to yield dolichol pyrophosphate (DolPP)-bound GlcNAc-1-phosphate. Six additional nucleotide-activated sugarsare next added to yield heptasaccharide-charged DolPP. This moiety isthen flipped across the endoplasmic reticulum (ER) membrane to facethe ER lumen by an ATP-independent flippase that remains to bedescribed. At this point, seven more sugars, each delivered from adistinct DolP carrier charged on the cytoplasmic face of the ERmembrane and flipped to face the ER lumen, are added to yield a 14-member branched oligosaccharide that is ultimately transferred toselect Asn residues of a nascent polypeptide entering the ER lumenby the multimeric oligosaccharyltransferase, with Stt3 serving as thecatalytic subunit of the complex.

In Bacteria, where N-glycosylation is apparently restricted to onlycertain groups, the process involved has been best described in thepathogen Campylobacter jejuni [22,23]. Here, some 60 different proteinsare modified by a heptasaccharide assembled by a pathway reminiscentof its eukaryal counterpart. In C. jejuni, N-glycosylation begins with thegeneration of di-N-acetylbacillosamine-charged undecaprenol pyropho-sphate (UndPP) via the fusion of a UDP-charged version of the sugarwith undecaprenol phosphate on the cytoplasmic face of the plasmamembrane. Following glycan extension through the addition of sixmore sugars, the UndPP-linked heptasaccharide is flipped across themembrane in a reaction involving the ABC transporter PglK. Once onthe outer surface of the plasma membrane, the glycan is delivered toselect Asn residues of target proteins by PglB, the bacterial oligosac-charyltransferase.

In Archaea, where the first example of non-eukaryal N-glycosylationwas reported [24], the process remains the least well understood. Inpart, this is due to the fact that the vast majority of identified strainscannot be grown in the laboratory, and of the small number ofcultivatable strains, genetic tools are only available for few. Further-more, the N-linked glycans decorating archaeal glycoproteins demon-strate enormous variability in terms of composition and architecture,reflecting the variety of N-glycosylation processes employed in Archaea[19,25]. Still, what is known reveals that as in the other two domains,N-glycosylation in Archaea begins with the assembly of a glycan on oneor more phosphorylated dolichol carriers. For instance, the first foursugars of the N-linked pentasaccharide decorating glycoproteins in thehalophile (‘salt-loving’ organism) Haloferax volcanii (optimal growth in1.5–2.5 M NaCl [26]) are assembled on a common DolP carrier, whilethe final sugar is delivered from a distinct DolP [27]. As such, DolPserves both as lipid glycan carrier and glycan donor in this organism. Bycontrast, the similar N-linked pentasaccharide attached to glycoproteinsof a second haloarchaea also originating from the Dead Sea, Haloarculamarismortui (optimal growth in 3.5–4 M NaCl [28]), is completelyassembled on a single DolP carrier [29]. In yet another halophilicarchaea, Halobacterium salinarum (optimal growth in 3.9 M NaCl [30]),the surface (S)-layer glycoprotein, the building block of the S-layersurrounding the cell, is simultaneously modified by two distinct N-linked glycans, one initially assembled on DolP, the second on DolPP[31,32]. In the thermoacidophile Sulfolobus acidocaldarius (optimalgrowth at 80 °C and pH 2 [33]), DolPP is charged with the samehexasaccharide as N-linked to glycoproteins in this organism, as well asits derivatives, although DolP and hexose-charged DolP have also beendetected [34,35]. In the related species Sulfolobus solfataricus (optimalgrowth at 87 °C and pH 3.5–5 [36]), DolPP is charged with the first sixsugars of the heptasaccharide N-linked to glycoproteins in this organ-ism; the final sugar could thus be derived from hexose-charged DolP[37]. As such, it appears that N-glycosylation in Archaea relies on avariety of lipid-linked glycan processing strategies.

The dolichols and polyprenols that serve as lipid glycan carriersacross evolution (Fig. 1; Table 1) are examples of polyisoprenoids, afamily of hydrophobic polymers containing linearly linked isoprene

subunits, members of which are found in all organisms [38,39]. Whileboth contain up to 25 isoprene subunits and present a hydroxyl group atthe so-called α end, dolichols include a saturated α position isoprenesubunit, whereas polyprenols, including C55 undecaprenol, do not. Thedolichols used in eukaryal N-glycosylation can, however, be distin-guished from their archaeal counterparts in that all of the dolicholsshown to participate in archaeal N-glycosylation to date also present anadditional saturated isoprene subunit at the ω position, namely thatisoprene farthest from the α end of the molecule[27,29,32,34,35,37,40,41]. The significance of saturation of the ωposition isoprene is not clear, since in vitro studies revealed howC55,60 DolP saturated solely at the α position could be glycan-chargedusing enzymes involved in N-glycosylation in the methanogen Metha-nococcus voltae (grown in the laboratory in a 80% H2/20% CO2

atmosphere [42]). Moreover, this glycan-charged lipid could serve assubstrate for the archaeal oligosaccharyltransferase AglB. At the sametime, in the thermophile Pyrococcus horikoshii (optimal growth at 98 °C[43]), both undecaprenol phosphate and dolichol phosphate werereported to serve as substrates for DolP mannose synthase, the enzymethat charges DolP with mannose, raising questions as to the importanceof α position isoprene saturation in archaeal N-glycosylation [44].

3. The diversity of archaeal phosphodolichols

In addition to the saturated ω position isoprene subunit thatdifferentiates archaeal dolichol from the eukaryal version of this lipid,the dolichols employed in archaeal N-glycosylation also present variousspecies-specific characteristics. These differences are mostly manifestedin terms of dolichol length, degree of phosphorylation and the extent ofinternal isoprene subunit saturation (Fig. 2).

To date, phosphorylated dolichols, many charged with the sameglycans as N-linked to glycoproteins in the same species, have beendetected in Archaea representing several phenotypes and belonging todifferent phyla. The first phosphorylated dolichols detected in Archaeawere in Hbt. salinarum, soon after this halophile provided the firstexample of non-eukaryal N-glycosylation, namely the S-layer glycopro-tein [24,45,46]. Here, C55,60 DolP is modified by a sulfated tetra/pentasaccharide N-linked to ten N-glycosylation sites of the protein,while C55–60 DolPP is modified by a distinct sulfated pentasaccharidethat apparently assembles into a chain when linked to the Asn-2position of the protein [31,32,46,47]. It is, however, not knownwhether the chain of repeating sulfated pentasaccharides is assembledon a single DolPP carrier (and if so, on which side of the membrane)and only then transferred to the protein, or alternatively, whether suchpolymerization results from the transfer of the subunit glycan to theprotein from a series of glycan-charged DolPP carriers assembled on thecytoplasmic face of the membrane and then flipped to face the exterior,where N-glycosylation transpires [48].

Recently, saturation of the α and ω position isoprenes of Hbt.salinarum C55,60 DolP and C55,60 DolPP was demonstrated. In thesestudies, DolP was detected bearing a disaccharide precursor of thetetra/pentasaccharide, while DolPP was shown to be modified by thefirst four sugars of the repeating pentasaccharide; DollPP bearingrepeats of this glycan was not observed [32]. However, the firstdemonstration of dolichol saturation at both ends of the lipid wasreported in the case C55,60 DolP bearing a tetrasaccharide in Hfx.volcanii [40]. Much later, the tetrasaccharide attached to this DolP wasshown to modify at least one Asn of the S-layer glycoprotein when thecells were grown in 1.7 M NaCl [49], considered as low salinity for thishalophile [26]. Indeed, the most convincing evidence for the involve-ment of DolP in archaeal N-glycosylation has come from studies on Hfx.volcanii, where the deletion of genes encoding components of the N-glycosylation pathway yielded the same effects on the glycans linked toboth DolP and to a target protein, the S-layer glycoprotein [27].Subsequently, C55,60 DolP saturated at both the α and ω positionisoprenes was observed in other haloarchaea, namely Har. marismortui,

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Fig. 1. Lipid glycan carriers used across evolution.Examples of lipid glycan carriers from Eukarya (human C95 DolPP (trans3cis16 isoprenes) charged with the tetradecasaccharideGlcNAc2-Man9-Glc3 where Glc is glucose, GlcNAc is N-acetylglucosamine and Man is mannose), Bacteria (C. jejuni C55 UndPP (trans3cis8 isoprenes) charged with the heptasaccharideGalNAc-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 isgalacturonic 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 archaeallipids, the α position isoprene is saturated, whereas the ω position isoprene is saturated only in the archaeal lipid.

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

Eukarya Bacteria Archaea

Lipid glycan carrier DolPDolPP

UndPP DolPDolPP

Length C70–C105 C50–C60 C30–C70

Positions of saturated isoprenes α-position isoprene None α- and ω-position isoprenes; variablenumber of internal position isoprenes

Location ER membrane Plasma membrane Plasma membraneTopology of sugar addition Sugars added on both sides of the membrane Sugars added only on the cytosolic side of the

membraneSugars added on the cytosolic side of themembrane and in some species, on theexternal side of the membrane

Number of lipid glycan carriersused per N-glycosylation event

Multiple Single Single or more in some species

Chemical modification of lipid-linked glycan

No No In some species

Recycling after glycan transfer totarget protein

DolPP is dephosphorylated to DolP, flippedto face the ER lumen and recharged to yieldDolPP-glycan

UndPP is dephosphophorylated to UndP, flipped toface the cytoplasm and recharged to yield UndPP-glycan

Unknown

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where the lipid was modified by the same pentasaccharide as found onthe S-layer glycoprotein in this species [29], and Haloferax mediterranei,where the lipid was modified by a disaccharide [32]. Presently, nothingelse is known about N-glycosylation in Hfx. mediterranei.

Haloarchaea, such as those considered above, belong to theEuryarchaeota, one of the better-studied archaeal phyla [1,50]. Thesame phylum also includes the methanogens, namely Archaea able toreduce carbon dioxide with hydrogen to generate methane [51]. Todate, phosphorylated dolichols have only been characterized in twospecies. InMethanococcus maripaludis (grown in the laboratory in a 80%H2/20% CO2 atmosphere [52]), a lipid extract was shown to containC55 DolP saturated at two non-specified positions and modified by atrisaccharide that corresponds to a precursor of the tetrasaccharide N-linked to glycoproteins in this organism [53,54]. Moreover, the enzymethought to add the initial sugar to the lipid carrier inM. maripaludis wasshown to be more active when presented with C55,60 DolP rather thanwith longer C85–105 DolP, as found in eukaryotes [54]. In contrast, olderstudies conducted on Methanothermus fervidus (optimal growth at 83 °Cin a 80% H2/20% CO2 atmosphere [55]), where the S-layer glycopro-tein is modified by an N-linked hexasaccharide, detected sugar-mod-ified C55 DolPP [56].

In addition to halophiles and methanogens, the Euryarchaeota alsoinclude thermophilic archaea where phosphodolichols involved in N-glycosylation have been characterized, namely Pyrococcus furiosus andArchaeoglobus fulgidus. In P. furiosus (optimal growth at 100 °C [57]),

C60,65,70 DolP modified by glycans containing up to the first six sugarsfound in the N-linked heptasaccharide that decorates glycoproteins inthis organism was described [37,41]. As such, P. furiosus DolP is thelongest phosphodolichol involved in archaeal N-glycosylation known todate. More striking, however, was the finding that in addition to beingsaturated at the α and ω position isoprenes, P. furiosus DolP is alsosaturated at up to four more internal isoprene positions, with theseadditional sites of saturation being closer to the ω than the α end of themolecule. In A. fulgidus (optimal growth at 83 °C [58]), C55,60 DolPdisplays saturation of not only the α and ω position isoprenes but alsoof up to four additional internal isoprene positions [37]. Moreover, A.fulgidus DolP is apparently modified by two distinct heptasaccharides[37]. The different lipid-linked glycans could reflect the fact that A.fulgidus encodes multiple versions of the oligosaccharyltransferase AglB[59], responsible for the transfer of the glycan moiety from the lipidcarrier to select Asn residues of modified proteins (see below), raisingthe possibility that different versions of the enzyme process distinctglycan substrates.

In addition to the phosphodolichols involved in N-glycosylationstudied in representatives of the Euryarchaeota, these lipids have alsobeen considered in three members of a second well-studied archaealphylum, the Crenarchaeota [1,50]. S. acidocaldarius is the only cre-narchaeote for which insight into the N-glycosylation process isavailable. Here, C40,45,50 DolP, in some cases charged with one of threedifferent hexoses, and C45 DolPP modified by the hexasaccharide added

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 ofinternal isoprene subunit saturation. Shown are major phosphodolichol species used (or present) in N-glycosylation in different Archaea.

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to target proteins in N-glycosylation, as well as by glycans comprisingthe first four of five sugars of this structure, were detected [34,35]. In S.acidocaldarius DolP and DolPP, up to six isoprenes are saturated,including those at the α and ω positions. In the related thermoacido-phile S. solfataricus, C30 and C45 DolPP modified by the first six sugars ofthe N-linked heptasaccharide assembled in this species [60] andsaturated at the α and ω isoprene positions, as well as at up to fouradditional internal position isoprenes, were identified [37]. Moreover,it has been suggested that the two phosphodolichol glycan carriers usedin S. solfataricus N-glycosylation differ not only in length (C30 and C45)but also in terms of stereochemistry [37]. At the same time, Pyrobacu-lum calidifontis (optimal growth at 90–95 °C [61]) was reported tocontain C50,55 DolPP modified by a decasaccharide also shown to be N-linked to a glycopeptide generated by proteolytic digestion of amembrane fraction prepared from this organism [37]. Similarly to thephosphodolichols in other crenarchaeotes considered to date, P.calidifontis DolPP is saturated at the α position isoprene, at up to fiveinternal position isoprenes and at the ω position isoprene [37].

Despite the limited number of archaeal species in which phospho-dolichols either shown or likely to be involved in N-glycosylation havebeen characterized, general considerations on the use of these lipidsmay have already been revealed. With the exception of M. fervidus,where older technologies were employed, it would appear that N-glycosylation in the Euryarchaeota relies on DolP as glycan lipidcarrier, with the N-linked glycan either being assembled on a singleDolP carrier or alternatively, being assembled on the modified proteinfrom precursors delivered from at least two DolP carriers. In contrast,Crenarchaeota rely on DolPP as lipid glycan carrier, with DolP possiblyserving as the carrier of individual sugars either delivered to DolPP-linked precursors of N-linked glycans or to glycans already transferredfrom DolPP carriers to target protein Asn residues. As such, it wouldappear that euryarchaeotes rely on a more bacterial-like N-glycosyla-tion process, whereas crenarchaeotes rely on a process reminiscent ofthat employed in Eukarya. Indeed, phylogenetic analyses of knownArchaea position the Crenarchaeota proximal to the ancestor ofmodern-day eukaryotes [62,63].

In addition, the fact that DolP and DolPP from both thermophiliceuryarchaeotes and crenarchaeotes include saturated isoprenes atinternal positions points to dolichol isoprene reduction as beingimportant for survival at high temperatures. Such enhanced saturation,relative to what is seen in mesophilic archaea, would reduce themovement of phosphodolichols in the membranes of thermophilicarchaea, a property that could be important for the enzyme-mediatedprocessing of these glycan carriers. At the same time, dolichol lengthdoes not seem to be sensitive to temperature, since both the shortest(C30) and longest (C70) archaeal phosphodolichols known to date havebeen detected in thermophiles [37,41].

4. Phosphodolichol biosynthesis in Archaea

Phosphodolichol synthesis occurs in two stages [38,39]. In the firststage, the two building blocks of isoprenoid biogenesis, isopentenylpyrophosphate (IPP) and its isomer dimethylallyldiphosphate(DMAPP), are generated from acetyl CoA. This is followed by thesecond stage of dolichol biogenesis in which a series of condensationreactions between DMAPP and several IPP moieties occurs. Theresulting polymer is then further processed to yield the phosphorylateddolichols used in archaeal N-glycosylation.

The classic route for generating IPP and DMAPP is known as themevalonate pathway [64]. Here, three acetyl CoA molecules arecondensed and reduced using NADPH to yield mevalonate via thesequential actions of acetoacetyl-CoA thiolase, 3-hydroxy-3-methylglu-taryl (HMG)-CoA synthase and HMG-CoA reductase. Mevalonate issubsequently phosphorylated by mevalonate-5-kinase and phosphome-valonate kinase to yield mevalonate-5-phosphate and mevalonatepyrophosphate, respectively. The latter compound is processed by

mevalonate pyrophosphate decarboxylase to generate IPP, which isisomerized by IPP isomerase to yield DMAPP (Fig. 3).

Genomic analyses revealed the presence of the first four enzymes ofthe classic mevalonate pathway in Archaea, namely acetoacetyl-CoAthiolase, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)synthase, HMG-CoA reductase and mevalonate-5-kinase [65,66]. Sub-sequent efforts not only confirmed the functionality of archaealversions of these enzymes but also revealed unique properties in severalinstances. For example, Hfx. volcanii HMG-CoA reductase is regulated atthe transcription level by environmental salinity, pointing to a linkbetween the cell surroundings and the biosynthesis of isoprenoids,including phosphodolichols [67]. Moreover, Hfx. volcanii HMG-CoAreductase is the first such enzyme that is not sensitive to feedbackinhibition by its substrate, acetoacetyl-CoA [68]. Likewise, knownfeedback inhibitors of mevalonate-5-kinases do not inhibit the Metha-nosarcina mazei enzyme, making it the sole member of a third class ofmevalonate kinases defined on the basis of inhibition profile [69].

At the same time, genomic scanning failed to detect archaealhomologues of mevalonate pyrophosphate decarboxylase in mostspecies [65,66,70], suggesting the existence of an alternate route forthe conversion of mevalonate-5-phosphate to IPP. Initial support forthis hypothesis came with the identification of an isopentenyl phos-phate kinase in Methanocaldococcus jannaschii (optimal growth at 85 °Cin a 80% H2/20% CO2 atmosphere; first isolated from a hydrothermalvent on the Pacific Ocean floor [71]), namely an enzyme thatsynthesizes IPP via the phosphorylation of isopentenyl phosphate[72]. Genomic analyses revealed that other Archaea also contain thegene encoding this protein, with the activity of recombinant isopente-nyl phosphate kinase from Methanothermobacter themautotrophicus(optimal growth at 65–70 °C in a 80% H2/20% CO2 atmosphere [73])and Thermoplasma acidophilum (optimal growth at 59 °C and pH 1–2[74]) having been demonstrated [75]. Subsequent efforts uncovered theexistence of both phosphomevalonate decarboxylase, responsible forconverting mevalonate-5-phosphate into isopentenyl phosphate, andisopentenyl phosphate kinase in Hfx. volcanii, thereby confirmed theexistence of an alternate route for IPP biosynthesis in Archaea (Fig. 3)[76]. Nonetheless, there are archaeal species that rely on the classicmevalonate pathway despite also encoding components of the alternatepathway, such as S. solfataricus [77]. Here too, Archaea have introducedunusual variations not seen elsewhere. For instance, while the meva-lonate pyrophosphate decarboxylase in S. solfataricus exists as a dimer,like its eukaryal and bacterial counterparts, the archaeal enzyme isunique in that a disulfide bond serves to stabilize the dimer in thisthermoacidophile [78]. Recently, evidence for the existence of yetanother pathway for IPP biosynthesis in Archaea has been presented. InT. acidophilum, mevalonate-3-kinase converts mevalonate into mevalo-nate-3-phosphate, which is then converted into mevalonate-3,5-bispho-sphate by mevalonate-3-phosphate-5-kinase [79,80]. Mevolonate-3-kinase was subsequently described in Picrophilus torridus (optimalgrowth at 60 °C and pH 1.8–2 [81]), with sequence analysis suggestingthe enzyme to also exist in other members of the Thermoplasmatales, theorder that includes these two species [82]. Presently, however, themevalonate-3,5-bisphosphate decarboxylase that would be required forthe appearance of IPP by this novel route has yet to be identified(Fig. 3). Finally, the IPP isomerases used by Archaea to convert IPP intoDMAPP are, for the most part, orthologs of a bacterial, rather than theeukaryal version of this enzyme [83]. This, despite the fact that manyBacteria do not use the MVA pathway but rather rely on a distinctpathway for IPP biosynthesis termed the MEP/DOXP pathway, as doplants [84,85]. Members of the archaeal order Halobacteriales, however,encode both versions of the isomerase [66].

To generate phosphodolichols from the five-carbon precursors IPPand DMAPP, there is a need for elongation steps in which DMAPP andmultiple IPP moieties polymerize to yield an isoprenoid chain, depho-sphorylation steps to yield a polyprenol, saturation steps to reduce theisoprene subunit at the α end of the dolichol molecule (and, in Archaea,

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the isoprene subunit at the ω position, and in some cases, at moreinternal positions) and finally, phosphorylation steps. While the detailsof many of these reactions are relatively well described in Eukarya (andin undecaprenol synthesis in Bacteria, where saturation steps are notrequired), much less is known about the route(s) taken in Archaea.

Polyprenol biosynthesis begins with DMAPP serving as the acceptorfor an IPP molecule to generate C10 geranyl pyrophosphate [38,39].This reaction, as well as the addition of a second IPP to generate C15

farnesyl pyrophosphate, involves trans-condensations catalyzed byisoprenyl pyrophosphate synthases, also termed prenyltransferases,members of an enzyme family responsible for generating polyprenolchains of increasing length [86]. Following the condensation of IPPmoieties in trans, additional IPP units are added in cis by a cis-prenyltransferase to generate a trans/cis-polyprenol pyrophosphate.

Now found within the membrane, the polyprenol pyrophosphate isnext thought to undergo two rounds of dephosphorylation to yieldpolyprenol [87,88]. In Eukarya, saturation of the α position isoprenesubunit is proposed to occur at this stage, yielding dolichol; in Bacteria,no such saturation occurs. Finally, dolichol is phosphorylated bydolichol kinase to generate DolP [87,89]. In Bacteria, an undecaprenolphosphokinase that catalyzes a similar reaction has been described[38,90]. Whereas there is considerable understanding of the steps takento synthesize IPP and DMAPP in Archaea, insight into how Archaeaassemble phosphodolichol from these building blocks remains onlypartial. Nonetheless, what is currently known has revealed unexpectedaspects of each of the latter steps of phosphodolichol assembly, namelyelongation, dephosphorylation, saturation and phosphorylation.

The sequential addition of IPP subunits to a DMAPP acceptor is

Fig. 3. Pathways of isopentenyl pyrophosphate biosynthesis in Archaea. In Archaea, isopentenyl pyrophosphate can be synthesized by different pathways. In the classic mevalonatepathway, 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 undergoesphosphorylation 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 isphosphorylated 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 bephosphorylated at the 5 position to produce IPP.

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catalyzed by distinct prenyltransferases that catalyze condensationreactions as a function of substrate length [86]. To generate dolichol,the so-called short-chain prenyltransferases are required [91]. In mostArchaea, the only members of this group are C20 geranylgeranylpyrophosphate synthases [92,93]. These, however, can assembletrans-polyprenol pyrophosphates of different lengths, as exemplifiedby the bi-functional enzyme from M. themautotrophicus that is able tosynthesize both farnesyl pyrophosphate and geranylgeranyl pyropho-sphate [94]. Similar bi-functional activity was reported for geranylger-anyl pyrophosphate synthases from S. acidocaldarius and Thermococcuskodakarensis (optimal growth at 95 °C [95]) [96,97]. Based on suchobservations, it has been proposed that archaeal geranylgeranylpyrophosphate synthases represent the ancestor of the farnesyl pyr-ophosphate synthases and geranylgeranyl pyrophosphate synthasespresently found in Eukarya and Bacteria [98,99]. This hypothesis has,however, been questioned by others [100]. Finally, in S. acidocaldarius,genes encoding IPP isomerase (saci0091), geranylgeranyl pyropho-sphate synthase (saci0092) and AglH, the glycosyltransferase respon-sible for adding the first sugar of the N-linked glycan to DolPP(saci0093), lay adjacent to each other in the genome, with saci0092and saci0093 being found on the same polycistronic mRNA [101,102].This gene arrangement offers support for close interplay betweenphosphodolichol biosynthesis and N-glycosylation in this thermoacido-phile.

In general, the substrate (or primer) of cis-prenyltransferases inEukarya and Bacteria is C15 trans-farnesyl pyrophosphate [38,39,91],although evidence for the broader selectively of these enzymes in plantshas been offered [103,104]. In Archaea, both C15 trans-farnesylpyrophosphate and C20 trans-geranylgeranyl pyrophosphate serve ascis-prenyltransferase substrates [92]. In S. acidocaldarius, apparentlyonly trans-geranylgeranyl pyrophosphate serves this role [92]. Therecent report of one of the three cis-prenyltransferases in Methanosarci-na acetivorans being able to catalyze both head-to-tail and non-head-to-tail condensation reactions [105] could reflect yet another uniqueaspect of archaeal phosphodolichol biosynthesis. In the hyperthermo-phile Aeropyrum pernix (optimal growth at 90–95 °C [106]), the cis-prenyltransferase is unusual in that the substrate is C25 trans-geranyl-farnesyl pyrophosphate [107]. This could indicate the use of a uniquelipid glycan carrier in this species. Accordingly, it is of note that when168 archaeal genomes were considered for the presence of aglB,encoding the archaeal oligosaccharyltransferase responsible for thetransfer of glycans from phosphodolichol carriers to target proteinAsn residues, A. pernix was only one of two species where no such genewas detected, raising the question of whether N-glycosylation occurs inthis organism [108]. However, if N-glycosylation indeed occurs in A.pernix, the process may rely on an oligosaccharyltransferase distinctfrom AglB. Lastly, it has been reported that in mammalian cells, cis-prenyltransferases require interaction with the NogoB receptor forstabilization of the enzyme [109]. In plants, where cis-prenyltrans-ferases exist as enzyme families, it was shown that select familymembers that contribute to dolichol biogenesis also interact with aNogoB receptor homologue [103,110]. Although phylogenetic analysishas raised the possibility of such a protein in Archaea [105], evidencefor the involvement of a NogoB receptor homologue in archaeal cis-prenyltransferase activity has yet to be presented.

Once the polyprenol pyrophosphates destined to become phospho-dolichols have been assembled, it is believed that they must nextundergo dephosphorylation, saturation and phosphorylation [111],although conclusive evidence that this is indeed the order of eventsin Archaea remains wanting. With this in mind, a scheme of the possiblesteps taken during the latter phase of archaeal DolP biosynthesis, usingS. acidocaldarius as a model system [34], is presented in Fig. 4. Indeed,it should be noted that alternate pathways leading to the appearance ofDolP exist in other forms of life [112], and, therefore, possibly inArchaea as well. Nonetheless, in this review it is assumed that inArchaea, polyprenol pyrophosphates are subjected to dephosphoryla-

tion, saturation and then phosphorylation to generate DolP.The conversion of polyprenol pyrophosphates to polyprenol re-

quires dephosphorylation. In Eukarya, the enzyme(s) responsible has(have) yet to be described, although polyprenol pyrophosphate phos-phatase and polyprenol phosphatase activities have been observed inwhole-cell homogenates [113]. In Bacteria, undecaprenol pyropho-sphate is converted to undecaprenol phosphate by the actions of UppP[114]. The resulting mono-phosphorylated polymer serves as thebacterial lipid glycan carrier. In Archaea, it is assumed that depho-sphorylation also occurs. Indeed, undecaprenol (and dolichol) has beenobserved in M. acetivorans [115]. Likewise, the detection of dolichol inS. acidocaldarius [34] could reflect the initial dephosphorylation ofpolyprenol pyrophosphates, although here too, the enzyme(s) respon-sible remain(s) to be identified. Finally, while roles for polyprenol anddolichol have been proposed in Bacteria and Eukarya, respectively[17], it is not known whether dolichol serves any biological function inArchaea.

In the presumed next step in phosphodolichol biosynthesis, satura-tion of the isoprene subunit found at the α position of polyprenol isthought to occur. In Archaea, saturation of the isoprene subunit at the ωposition would likely also occur at this point, as would the saturation ofother isoprene subunits found at more internal positions in those inspecies where highly saturated phosphodolichols exist. A polyprenolreductase responsible for saturation of the α position isoprene subunitof polyprenol has been identified in Eukarya [116]. The enzyme,encoded by the SRD5A3 gene in humans, has no archaeal homologue.As such, it would appear that Archaea rely on a distinct enzyme for suchactivity. Furthermore, given that eukaryal cells lacking SRD5A3 canstill generate some 30% of the dolichol found in normal cells [116], itwould seem that at least one more eukaryal polyprenol reductase mustexist. One can speculate that Archaea, lacking a SRD5A3 gene, couldinstead contain homologues of this(these) additional polyprenol re-ductase(s), considering the high number of saturated isoprenes inarchaeal phosphodolichols. To date, archaeal proteins showing poly-prenol reductase activity have been described. S. acidocaldarius con-tains a geranylgeranyl reductase that is able to saturate three of the fourdouble bonds in geranylgeranyl pyrophosphate, leaving the Δ2 doublebond intact and thereby yielding a substrate for prenyltransferases in areaction that would result in the removal of the pyrophosphate groupfrom the geranylgeranyl pyrophosphate substrate [117]. Recent crystal-lographic analysis of S. acidocaldarius geranylgeranyl reductase boundto geranylgeranyl pyrophosphate has provided insight into the catalyticmechanism of this enzyme [118]. In contrast to the geranylgeranylreductase of T. acidophilum, which uses NADPH as electron donor[119], the S. acidocaldarius enzyme does not use either NADPH orNADH, and as such, the source of electrons used in the saturationreaction in this species is not known [117]. In the case of M. acetivoransgeranylgeranyl reductase, ferrodoxin is thought to serve as electrondonor [120]. In addition, reductases that saturate the ω positionisoprene subunit of polyprenol, all members of the geranylgeranylreductase family, have also been identified. These enzymes, however,affect the saturation status of other lipids as well, raising the question ofwhether these reductases are truly components of the phopshodolicholbiosynthesis pathway in Archaea [115,121]. Indeed, the observationthat S. acidocaldarius contains versions of C45 DolP presenting satura-tion at the α position isoprene subunit, at the α and ω position isoprenesubunits and at these two positions together as well as at one-four moreinternal positions, suggests that multiple reductases contribute tophosphodolichol biosynthesis here [34]. Finally, considering that twoor more of the isoprene subunits comprising archaeal dolichols aresaturated, it has been proposed that archaeal dolichols should be calledarchaeoprenols, so as to distinguish them from their less saturatedeukaryal counterparts [122].

In what is assumed to be the final step of DolP biosynthesis, dolicholis phosphorylated. In Eukarya, this reaction is catalyzed by a CTP-dependent dolichol kinase [123,124]. Homology-based searches of

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archaeal genomes have identified homologues of eukaryal dolicholkinase in only a limited number of species, implying that dolicholphosphorylation in Archaea relies on a distinct enzyme.

Once the lipid-linked glycan has been transferred by the oligosac-charyltransferase to a target protein, the lipid carrier can be recycledfor subsequent rounds of glycan-charging. In Eukarya, for example, theDolPP that remains following N-glycosylation undergoes dephosphor-ylation to yield DolP, which is subsequently returned to the cytoplasmicleaflet of ER, where it is again recruited as a glycan carrier [125,126].In Archaea, incubation of glycan-charged DolPP from S. solfataricus orP. calidifontis with a membrane fraction containing the oligosaccharyl-transferase AglB and an peptide that contained an Asn residue suitablefor glycosylation resulted in the appearance of DolP, suggesting that adephosphorylation reaction, similar to that which occurs in Eukarya,also transpires in Archaea where DolPP serves as the lipid glycan carrier[37]. Indeed, externally oriented pyrophosphatases from S. acidocaldar-ius and Sulfolobus tokodaii (optimal growth at 80 °C and pH 2.5–3[127]) have been described and proposed to participate in DolPPrecycling [128–130].

5. Phosphodolichol-processing enzymes that participate inarchaeal N-glycosylation

In terms of both glycan composition and glycan architecture,archaeal N-glycosylation presents a degree of diversity not seen ineither Eukarya or Bacteria [19]. Fittingly, what is known of archaeal N-glycosylation pathways reveals the involvement of numerous species-specific components [25]. In contrast, the oligosaccharyltransferaseAglB is highly conserved across Archaea. Indeed, like PglB, the bacterialoligosaccharyltransferase, and Stt3, the catalytic subunit of the eu-karyal oligosaccharyltransferase, AglB also contains the WWDXG andother motifs important for activity. AglB, moreover, presents a topologysimilar to those of PglB and Stt3 [131,132]. Solution of the crystalstructures of the complete AglB protein from A. fulgidus, as well as ofthe catalytic domain from P. furiosus and those of the three A. fulgidusAglB paralogs by the Kohda group [131,133–135] has not onlyprovided insight into how AglB catalyzes the glycosylation of targetAsn residues but also into how the enzyme interacts with the glycan-bearing phosphodolichol carrier. Analysis of the electron density mapof full-length A. fulgidus AglB revealed substantial electron density,modeled as a sulfate ion, 5 Å from the zinc ion found in the catalytic siteof the enzyme (that, during the crystallization process, had apparently

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 synthesizingphosphodolichols in Archaea. Initially (not shown), three isopentenyl pyrophosphates and dimethylallyldiphosphate combine to form geranylgeranyl pyrophosphate (GGPP). Whereinternal 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 ofdolichol 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 undergophosphorylation to yield dolichol phosphate (DolP). Alternatively, polyprenol pyrophosphate could undergo reduction reactions, followed by removal of one phosphate group to yieldDolP or both phosphate groups, followed by re-phosphorylation, again yielding DolP, as thought to occur in Eukarya. Abbreviations used: DolP, dolichol phosphate; DolPP, dolicholpyrophosphate; GGPP, geranylgeranyl pyrophosphate.

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replaced the magnesium ion normally associated with the enzyme)[135]. This sulfate group interacted with His-81, His-162, Trp-215 andArg-246, residues that are conserved in other AglB sequences. Site-directed mutagenesis showed the importance of the positive charges ofHis-81, His-162 and Arg-246. Based on these observations, it wasassumed that the sulfate ion mimicked the phosphate group of the DolPthat serves as the glycan lipid carrier in A. fulgidus N-glycosylation [37].Accordingly, a docking model showed a good fit of the DolP dolicholchain within the hydrophobic groove on the protein surface leading tothese residues. Once a crystal structure of AglB from an archaeal speciesthat relies on DolPP as glycan lipid carrier becomes available, it will beof interest to see if the same architecture applies.

Flippases, catalyzing the translocation of glycan-charged and gly-can-free phosphodolichols across the membrane [136], are also com-ponents of N-glycosylation pathways in intimate contact with DolPand/or DolPP. In Archaea, the only known protein proposed to act as aflippase or to play a flippase-assisting role is Hfx. volcanii AglR [137].Upon deletion of the encoding gene, only the first four sugars of the N-linked pentasaccharide normally decorating glycoproteins in thisspecies were protein-bound. It was previously shown that this tetra-saccharide is assembled on a single DolP carrier, while the fifth sugar(mannose) is derived from its own DolP carrier [27]. Moreover, in theaglR-deleted strain, mannose-charged DolP accumulated. As such, itwould appear that AglR is involved in translocating mannose-chargedDolP across the membrane. Accumulation of tetrasaccharide-chargedDolP was, however, also noted in the absence of AglR, pointing to amore general flippase or flippase-related role for the protein. Furthersupport for AglR acting as a flippase or playing a flippase-supportingrole comes from sequence homology searches that revealed thesimilarity of AglR to Wzx proteins. In Bacteria, members of this groupof proteins are thought to act as flippases responsible for translocatinglipid-linked O-antigen precursor oligosaccharides across the membraneduring lipopolysaccharide biosynthesis [138].

6. Conclusions and future prospects

Until recently, the study of Archaea had been hampered by theinability to cultivate the vast majority of identified strains in thelaboratory, as well as the few cultivatable strains for which genetictools were available. However, as recent advances have expanded thelist of species amenable to molecular studies, it is likely that novelsolutions employed by these unusual organisms to address a variety ofbiological challenges will be revealed. In terms of phosphodolichols, itis conceivable that not only will the enzymes catalyzing all of the stepsof known pathways be defined but that additional archaeal-specificsteps will be identified. In addition, other more specific mysteries maybe solved. For instance, both DolP and DolPP serve as lipid glycancarriers in Hbt. salinarum [31]. It is presently unclear whether both areprocessed by the same oligosaccharyltransferase. Since genome analysisreveals only a single aglB gene in this organism [58,108], it is possiblethat a novel oligosaccharyltransferase will be identified. Indeed, studieson Hfx. volcanii N-glycosylation suggest that such an enzyme exists[49].

In summary, life in extreme conditions, such as those encounteredby many Archaea, often calls for unique biological solutions. The routesused for archaeal N-glycosylation and the biosynthesis of the phospho-dolichols used as lipid glycan carriers in this post-translational mod-ification have provided and will likely continue to provide novelexamples of Nature's creativity in the face of such challenges.

Transparency document

The http://dx.doi.org/10.1016/j.bbalip.2017.03.005 associatedwith this article can be found, in online version.

Acknowledgements

J.E. was supported by grants from the Israel Science Foundation(ISF) (grant 109/16), the ISF within the ISF-UGC joint research programframework (grant 2253/15), the ISF-NSFC joint research program(grant 2193/16) and the German-Israeli Foundation for ScientificResearch and Development (grant I-1290-416.13/2015). Z.G. wassupported by the LIPID MAPS Large Scale Collaborative Grant (GM-069338) and grant EY023666 from NIH.

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