Virus Budding and the ESCRT Pathway
2013; Cell Press; Volume: 14; Issue: 3 Linguagem: Inglês
10.1016/j.chom.2013.08.012
ISSN1934-6069
AutoresJörg Votteler, Wesley I. Sundquist,
Tópico(s)Lipid Membrane Structure and Behavior
ResumoEnveloped viruses escape infected cells by budding through limiting membranes. In the decade since the discovery that HIV recruits cellular ESCRT (endosomal sorting complexes required for transport) machinery to facilitate viral budding, this pathway has emerged as the major escape route for enveloped viruses. In cells, the ESCRT pathway catalyzes analogous membrane fission events required for the abscission stage of cytokinesis and for a series of “reverse topology” vesiculation events. Studies of enveloped virus budding are therefore providing insights into the complex cellular mechanisms of cell division and membrane protein trafficking (and vice versa). Here, we review how viruses mimic cellular recruiting signals to usurp the ESCRT pathway, discuss mechanistic models for ESCRT pathway functions, and highlight important research frontiers. Enveloped viruses escape infected cells by budding through limiting membranes. In the decade since the discovery that HIV recruits cellular ESCRT (endosomal sorting complexes required for transport) machinery to facilitate viral budding, this pathway has emerged as the major escape route for enveloped viruses. In cells, the ESCRT pathway catalyzes analogous membrane fission events required for the abscission stage of cytokinesis and for a series of “reverse topology” vesiculation events. Studies of enveloped virus budding are therefore providing insights into the complex cellular mechanisms of cell division and membrane protein trafficking (and vice versa). Here, we review how viruses mimic cellular recruiting signals to usurp the ESCRT pathway, discuss mechanistic models for ESCRT pathway functions, and highlight important research frontiers. Cell membranes present significant dissemination barriers, and viruses have therefore developed sophisticated mechanisms for entering and exiting cells. Here, we review how enveloped viruses bud through membranes and thereby acquire their lipid bilayers, with a particular focus on viruses that employ the ubiquitous strategy of usurping the cellular ESCRT (endosomal sorting complexes required for transport) pathway. Although ESCRT-dependent budding is best studied for retroviruses, particularly HIV-1, a remarkable variety of enveloped viruses use this pathway to escape cells (Table S1). Comparative virology is providing important insights not only into virology, but also into the cellular functions and mechanisms of the ESCRT machinery (reviewed in Agromayor and Martin-Serrano, 2013Agromayor M. Martin-Serrano J. Knowing when to cut and run: mechanisms that control cytokinetic abscission.Trends Cell Biol. 2013; 23: 433-441Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar, Hanson and Cashikar, 2012Hanson P.I. Cashikar A. Multivesicular Body Morphogenesis.Annu. Rev. Cell Dev. Biol. 2012; 28: 337-362Crossref PubMed Scopus (43) Google Scholar, Henne et al., 2011Henne W.M. Buchkovich N.J. Emr S.D. The ESCRT pathway.Dev. Cell. 2011; 21: 77-91Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar, Hurley and Hanson, 2010Hurley J.H. Hanson P.I. Membrane budding and scission by the ESCRT machinery: it’s all in the neck.Nat. Rev. Mol. Cell Biol. 2010; 11: 556-566Crossref PubMed Scopus (213) Google Scholar, McCullough et al., 2013McCullough J. Colf L.A. Sundquist W.I. Membrane fission reactions of the mammalian ESCRT pathway.Annu. Rev. Biochem. 2013; 82: 663-692Crossref PubMed Scopus (21) Google Scholar, Weissenhorn et al., 2013Weissenhorn W. Poudevigne E. Effantin G. Bassereau P. How to get out: ssRNA enveloped viruses and membrane fission.Curr Opin Virol. 2013; 3: 159-167Crossref PubMed Scopus (5) Google Scholar). This approach is particularly powerful because ESCRT pathways are conserved across Eukarya and are even found in Archaea; for example, in crenarchaeal hyperthermophiles such as Sulfolobus solfataricus, the ESCRT pathway is used for egress of the enveloped sulfolobus turreted icosahedral virus (STIV) (Snyder et al., 2013Snyder J.C. Samson R.Y. Brumfield S.K. Bell S.D. Young M.J. Functional interplay between a virus and the ESCRT machinery in Archaea.Proc. Natl. Acad. Sci. USA. 2013; 110: 10783-10787Crossref PubMed Scopus (6) Google Scholar). Enveloped viruses commonly assemble and bud at the plasma membrane, although some bud into internal compartments (Lorizate and Kräusslich, 2011Lorizate M. Kräusslich H.G. Role of lipids in virus replication.Cold Spring Harb. Perspect. Biol. 2011; 3: a004820Crossref Scopus (7) Google Scholar). In the latter cases, the internal compartment must ultimately fuse with the plasma membrane to release the virus from the cell. The topology of virus budding differs from classical cellular vesiculation processes such as endocytosis, where the membrane constricts away from the cytoplasm and membrane fission is catalyzed by cytoplasmic dynamin, which acts from the outside of the bud neck. In contrast, the membranes of budding viruses must be constricted toward the cytoplasm, and cytoplasmic host factors that catalyze membrane fission must work from within the bud neck. The ESCRT pathway remains the only well-characterized cellular pathway known to perform such “reverse topology” membrane fission events, and this capability seems to explain why so many different viruses have evolved to usurp this machinery. Conceptually, virus budding can be divided into two stages: (1) membrane deformation, when the membrane is “wrapped” around the assembling virion, and (2) membrane fission, when the bud neck is severed. The structural proteins of enveloped viruses typically bind membranes and form spherical or helical assemblies. Thus, assembly and budding are often inextricably linked processes. It has generally been assumed that the energy provided by protein-protein and protein-membrane interactions is sufficient to drive membrane envelopment, although there are intriguing hints that cellular factors may sometimes be recruited to help with membrane bending, much as membrane bending proteins cooperate with clathrin scaffolds to create endosomal vesicles (McMahon and Boucrot, 2011McMahon H.T. Boucrot E. Molecular mechanism and physiological functions of clathrin-mediated endocytosis.Nat. Rev. Mol. Cell Biol. 2011; 12: 517-533Crossref PubMed Scopus (316) Google Scholar). The ESCRT machinery then typically draws the opposing membranes together and mediates the final membrane fission step required for virus release. The different stages of virus budding are nicely illustrated by the process of HIV-1 assembly (Sundquist and Kräusslich, 2012Sundquist W.I. Kräusslich H.G. HIV-1 assembly, budding, and maturation.Cold Spring Harb Perspect Med. 2012; 2: a006924Crossref Scopus (66) Google Scholar). As in other retroviruses, the HIV-1 Gag polyprotein functions as the major viral structural protein. Gag is targeted to the inner leaflet of the plasma membrane by a bipartite signal comprising an N-myristoyl fatty acid modification and a binding site for the plasma membrane-specific phosphatidyl inositol, PI(4,5)P2. Gag molecules capture the viral RNA genome and assemble into a spherical virion that is organized on a semiregular hexagonal net (Bharat et al., 2012Bharat T.A. Davey N.E. Ulbrich P. Riches J.D. de Marco A. Rumlova M. Sachse C. Ruml T. Briggs J.A. Structure of the immature retroviral capsid at 8 Å resolution by cryo-electron microscopy.Nature. 2012; 487: 385-389Crossref PubMed Scopus (36) Google Scholar). Recombinant HIV-1 Gag molecules can form spherical particles in vitro, and Gag assembly can therefore contribute to the energy required for membrane deformation (Campbell and Rein, 1999Campbell S. Rein A. In vitro assembly properties of human immunodeficiency virus type 1 Gag protein lacking the p6 domain.J. Virol. 1999; 73: 2270-2279Crossref PubMed Google Scholar). Under some conditions, however, retroviral assembly can arrest before fully spherical virions are formed, suggesting that host factors may also participate in membrane deformation and Gag assembly (Dooher et al., 2007Dooher J.E. Schneider B.L. Reed J.C. Lingappa J.R. 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Assembling HIV-1 Gag molecules also recruit early-acting factors of the ESCRT pathway required to complete the membrane fission step. In the absence of ESCRT factor recruitment, virus assembly typically arrests at a late stage in which the fully assembled viral Gag shell remains connected to the plasma membrane through a thin membrane “stalk” (Göttlinger et al., 1991Göttlinger H.G. Dorfman T. Sodroski J.G. Haseltine W.A. Effect of mutations affecting the p6 gag protein on human immunodeficiency virus particle release.Proc. Natl. Acad. Sci. USA. 1991; 88: 3195-3199Crossref PubMed Google Scholar). Thus, the ESCRT pathway functions primarily to mediate the membrane fission step required for virion release. In the following, we discuss components and functions of the ESCRT pathway, describe key insights gathered from virology, and outline important next steps for future research. The ESCRT pathway was initially identified through genetic analyses in yeast that defined the factors required to target membrane proteins for degradation within vacuoles (or lysosomes in mammalian cells) (Hanson and Cashikar, 2012Hanson P.I. Cashikar A. Multivesicular Body Morphogenesis.Annu. Rev. Cell Dev. Biol. 2012; 28: 337-362Crossref PubMed Scopus (43) Google Scholar, Henne et al., 2011Henne W.M. Buchkovich N.J. Emr S.D. The ESCRT pathway.Dev. Cell. 2011; 21: 77-91Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar). Such ubiquitylated membrane proteins are sorted into vesicles that bud inward into the lumen of maturing endosomes or multivesicular bodies (MVB) and are then degraded when the MVB fuses with the vacuole. As illustrated in Figure 1, the MVB vesiculation/trafficking pathway is expanded in mammalian cells because MVBs can either fuse with lysosomes to release vesicle contents for degradation or fuse with the plasma membrane to release extracellular exosomes (Akers et al., 2013Akers J.C. Gonda D. Kim R. Carter B.S. Chen C.C. Biogenesis of extracellular vesicles (EV): exosomes, microvesicles, retrovirus-like vesicles, and apoptotic bodies.J. Neurooncol. 2013; 113: 1-11Crossref PubMed Scopus (14) Google Scholar, Raposo and Stoorvogel, 2013Raposo G. Stoorvogel W. Extracellular vesicles: exosomes, microvesicles, and friends.J. Cell Biol. 2013; 200: 373-383Crossref PubMed Scopus (120) Google Scholar). Since the initial discovery that HIV-1 usurps the ESCRT pathway to bud from the plasma membrane (Demirov et al., 2002Demirov D.G. Ono A. Orenstein J.M. Freed E.O. Overexpression of the N-terminal domain of TSG101 inhibits HIV-1 budding by blocking late domain function.Proc. Natl. Acad. Sci. 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These different ESCRT-dependent processes share the same reverse topology and produce small vesicles of similar sizes (30–120 nm), but differ in the target membrane from which vesiculation occurs (endosome versus plasma membrane), the site of vesicle release (lysosome versus extracellular space), and/or the cargo (membrane proteins versus exosomal cargoes versus viral genomes). In 2007, Martin-Serrano and colleagues demonstrated that the ESCRT pathway also severs the thin intercellular bridges that connect daughter cells during the final step of cell division (termed abscission) (Agromayor and Martin-Serrano, 2013Agromayor M. Martin-Serrano J. Knowing when to cut and run: mechanisms that control cytokinetic abscission.Trends Cell Biol. 2013; 23: 433-441Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar, Carlton and Martin-Serrano, 2007Carlton J.G. Martin-Serrano J. Parallels between cytokinesis and retroviral budding: a role for the ESCRT machinery.Science. 2007; 316: 1908-1912Crossref PubMed Scopus (314) Google Scholar, Fededa and Gerlich, 2012Fededa J.P. Gerlich D.W. Molecular control of animal cell cytokinesis.Nat. Cell Biol. 2012; 14: 440-447Crossref PubMed Google Scholar). This unexpected discovery emerged from their work on HIV budding and beautifully illustrates how analyses of host-microbe interactions can illuminate important cell biology (and vice versa). Abscission appears to have been the primordial ESCRT pathway function because crenarchaeal organisms that lack internal membranes nevertheless use a primitive ESCRT pathway to divide (Samson and Bell, 2009Samson R.Y. Bell S.D. Ancient ESCRTs and the evolution of binary fission.Trends Microbiol. 2009; 17: 507-513Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar). During abscission, the ESCRT pathway again mediates membrane fission from the cytoplasmic face of the intercellular bridge, but the membrane must be constricted over a much larger distance, starting from a diameter of ∼1 μm in mammalian cells. Moreover, ESCRT pathway functions must be integrated with other complex mitotic processes, including cleavage furrow ingression, microtubule severing, chromosome segregation, and the abscission checkpoint (Agromayor and Martin-Serrano, 2013Agromayor M. Martin-Serrano J. Knowing when to cut and run: mechanisms that control cytokinetic abscission.Trends Cell Biol. 2013; 23: 433-441Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar, Fededa and Gerlich, 2012Fededa J.P. Gerlich D.W. Molecular control of animal cell cytokinesis.Nat. Cell Biol. 2012; 14: 440-447Crossref PubMed Google Scholar, McCullough et al., 2013McCullough J. Colf L.A. Sundquist W.I. Membrane fission reactions of the mammalian ESCRT pathway.Annu. Rev. Biochem. 2013; 82: 663-692Crossref PubMed Scopus (21) Google Scholar). The complexity of cytokinesis, together with the variety of different ESCRT pathway functions, seems to explain why the mammalian ESCRT pathway has more than 30 components, including multiple isoforms of nearly all core ESCRT factors. Although the ESCRT pathway functions as an integrated membrane fission machinery, three broad classes of factors are recruited sequentially to perform distinct functions: (1) adaptor proteins define sites of ESCRT action at specific membranes (Figure 1), (2) early-acting factors initiate ESCRT assembly and stabilize membrane curvature, and (3) late-acting factors mediate membrane constriction and fission. Examples of the growing list of ESCRT adaptors include HRS/STAM (MVB vesicles); viral structural proteins such as retroviral Gag proteins, arenaviral Z proteins, and filoviral VP40 proteins (viruses); CEP55 (abscission); ARRDC1 (shedding microvesicles); and Syntenin/Syndecan (exosomes) (Figure 1). These adaptors localize to different membranes and membrane domains—often by recognizing specific phospholipids—where they concentrate vesicle cargoes and recruit the early-acting ESCRT factors. Two different classes of early-acting ESCRT factors have been identified: Bro1 domain proteins and ESCRT-I/ESCRT-II complexes. Although distinct in architecture, these factors share several key mechanistic activities, including the ability to bind ubiquitin and recruit late-acting ESCRT-III subunits. ESCRT-III subunits then form filaments and recruit VPS4 ATPases, which together constrict membranes and mediate fission. The following sections summarize the structures and functions of core early- and late-acting ESCRT factors. We refer readers to other recent reviews for more comprehensive descriptions of the ESCRT machinery and full primary references (Agromayor and Martin-Serrano, 2013Agromayor M. Martin-Serrano J. Knowing when to cut and run: mechanisms that control cytokinetic abscission.Trends Cell Biol. 2013; 23: 433-441Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar, Hanson and Cashikar, 2012Hanson P.I. Cashikar A. Multivesicular Body Morphogenesis.Annu. Rev. Cell Dev. Biol. 2012; 28: 337-362Crossref PubMed Scopus (43) Google Scholar, Henne et al., 2011Henne W.M. Buchkovich N.J. Emr S.D. The ESCRT pathway.Dev. Cell. 2011; 21: 77-91Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar, Hurley and Hanson, 2010Hurley J.H. Hanson P.I. Membrane budding and scission by the ESCRT machinery: it’s all in the neck.Nat. Rev. Mol. Cell Biol. 2010; 11: 556-566Crossref PubMed Scopus (213) Google Scholar, McCullough et al., 2013McCullough J. Colf L.A. Sundquist W.I. Membrane fission reactions of the mammalian ESCRT pathway.Annu. Rev. Biochem. 2013; 82: 663-692Crossref PubMed Scopus (21) Google Scholar, Weissenhorn et al., 2013Weissenhorn W. Poudevigne E. Effantin G. Bassereau P. How to get out: ssRNA enveloped viruses and membrane fission.Curr Opin Virol. 2013; 3: 159-167Crossref PubMed Scopus (5) Google Scholar). ALIX is the founding member of a family of related Bro1 domain-containing mammalian proteins that also include HD-PTP, BROX, RHPN1, and RHPN2. ALIX is recruited by many viral structural proteins (Strack et al., 2003Strack B. Calistri A. Craig S. Popova E. Göttlinger H.G. AIP1/ALIX is a binding partner for HIV-1 p6 and EIAV p9 functioning in virus budding.Cell. 2003; 114: 689-699Abstract Full Text Full Text PDF PubMed Scopus (489) Google Scholar and Table S1) and also by CEP55 during cytokinesis (Carlton and Martin-Serrano, 2007Carlton J.G. Martin-Serrano J. Parallels between cytokinesis and retroviral budding: a role for the ESCRT machinery.Science. 2007; 316: 1908-1912Crossref PubMed Scopus (314) Google Scholar) and by Syndecan/Syntenin during exosome formation (Baietti et al., 2012Baietti M.F. Zhang Z. Mortier E. Melchior A. Degeest G. Geeraerts A. Ivarsson Y. Depoortere F. Coomans C. Vermeiren E. et al.Syndecan-syntenin-ALIX regulates the biogenesis of exosomes.Nat. Cell Biol. 2012; 14: 677-685Crossref PubMed Scopus (78) Google Scholar). These observations imply that ALIX can initiate ESCRT assembly. Recently, the yeast Bro1p homolog was shown to act early in the yeast MVB pathway, indicating that Bro1p is likely a true ALIX homolog (Pashkova et al., 2013Pashkova N. Gakhar L. Winistorfer S.C. Sunshine A.B. Rich M. Dunham M.J. Yu L. Piper R.C. The yeast Alix homolog Bro1 functions as a ubiquitin receptor for protein sorting into multivesicular endosomes.Dev. Cell. 2013; 25: 520-533Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar). Bro1 domains bind and recruit downstream ESCRT-III subunits of the CHMP4/Snf7p and CHMP5 families. ALIX Bro1 also can bind membranes, particularly lysobisphosphatidic acid (LBPA) (Bissig et al., 2013Bissig C. Lenoir M. Velluz M.C. Kufareva I. Abagyan R. Overduin M. Gruenberg J. Viral infection controlled by a calcium-dependent lipid-binding module in ALIX.Dev. 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Decoding the intrinsic mechanism that prohibits ALIX interaction with ESCRT and viral proteins.Biochem. J. 2010; 432: 525-534Crossref PubMed Scopus (13) Google Scholar), and (4) posttranslational modifications such as ubiquitylation (ALIX) and farnesylation (BROX). Mammals express a variety of heterotetrameric ESCRT-I complexes, each of which contains a single copy of the unique TSG101 subunit and single copies of one of the different isoforms of VPS28, VPS37, and MVB12/UBAP1 (McCullough et al., 2013McCullough J. Colf L.A. Sundquist W.I. Membrane fission reactions of the mammalian ESCRT pathway.Annu. Rev. Biochem. 2013; 82: 663-692Crossref PubMed Scopus (21) Google Scholar). ESCRT-I, in turn, can bind the heterotetrameric ESCRT-II complex, which contains single copies of EAP45 and EAP30, and two copies of EAP20. The large, crescent-shaped ESCRT-I/ESCRT-II supercomplex concentrates within the necks of budding vesicles (Boura et al., 2012Boura E. Różycki B. Chung H.S. Herrick D.Z. Canagarajah B. Cafiso D.S. Eaton W.A. Hummer G. Hurley J.H. Solution structure of the ESCRT-I and -II supercomplex: implications for membrane budding and scission.Structure. 2012; 20: 874-886Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar, Hurley and Hanson, 2010Hurley J.H. Hanson P.I. Membrane budding and scission by the ESCRT machinery: it’s all in the neck.Nat. Rev. Mol. Cell Biol. 2010; 11: 556-566Crossref PubMed Scopus (213) Google Scholar, Wollert and Hurley, 2010Wollert T. Hurley J.H. Molecular mechanism of multivesicular body biogenesis by ESCRT complexes.Nature. 2010; 464: 864-869Crossref PubMed Scopus (199) Google Scholar) and contains a series of accessory domains and motifs that can bind adaptors, ubiquitin, membranes, and specific phosphatidyl inositides (Henne et al., 2011Henne W.M. Buchkovich N.J. Emr S.D. The ESCRT pathway.Dev. Cell. 2011; 21: 77-91Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar, Hurley and Hanson, 2010Hurley J.H. 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