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When in Need of an ESCRT: the Nature of Virus Assembly Sites Suggests Mechanistic Parallels Between Nuclear Virus Egress and Retroviral Budding

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When in Need of an ESCRT: the Nature of Virus Assembly Sites Suggests Mechanistic Parallels Between Nuclear Virus Egress and Retroviral Budding viruses Review When in Need of an ESCRT: The Nature of Virus Assembly Sites Suggests Mechanistic Parallels between Nuclear Virus Egress and Retroviral Budding Kevin M. Rose 1,∗ , Stephanie J. Spada 2, Vanessa M. Hirsch 2 and Fadila Bouamr 2 1 Department of Molecular and Cell Biology, California Institute for Quantitative Biosciences, University of California—Berkeley, Berkeley, CA 94720, USA 2 Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Rockville, MD 20894, USA; [email protected] (S.J.S.); [email protected] (V.M.H.); [email protected] (F.B.) * Correspondence: [email protected] Abstract: The proper assembly and dissemination of progeny virions is a fundamental step in virus replication. As a whole, viruses have evolved a myriad of strategies to exploit cellular compartments and mechanisms to ensure a successful round of infection. For enveloped viruses such as retroviruses and herpesviruses, acquisition and incorporation of cellular membrane is an essential process during the formation of infectious viral particles. To do this, these viruses have evolved to hijack the host Endosomal Sorting Complexes Required for Transport (ESCRT-I, -II, and -III) to coordinate the sculpting of cellular membrane at virus assembly and dissemination sites, in seemingly different, yet fundamentally similar ways. For instance, at the plasma membrane, ESCRT-I recruitment is essential for HIV-1 assembly and budding, while it is dispensable for the release of HSV-1. Further, Citation: Rose, K.M.; Spada, S.J.; HSV-1 was shown to recruit ESCRT-III for nuclear particle assembly and egress, a process not used by Hirsch, V.M.; Bouamr, F. When in retroviruses during replication. Although the cooption of ESCRTs occurs in two separate subcellular Need of an ESCRT: The Nature of compartments and at two distinct steps for these viral lifecycles, the role fulfilled by ESCRTs at these Virus Assembly Sites Suggests sites appears to be conserved. This review discusses recent findings that shed some light on the Mechanistic Parallels between potential parallels between retroviral budding and nuclear egress and proposes a model where HSV-1 Nuclear Virus Egress and Retroviral nuclear egress may occur through an ESCRT-dependent mechanism. Budding. Viruses 2021, 13, 1138. https://doi.org/10.3390/v13061138 Keywords: enveloped virus budding; nuclear egress; ESCRT; membrane scission Academic Editor: Donald M. Coen Received: 22 April 2021 Accepted: 2 June 2021 1. Introduction Published: 13 June 2021 ESCRTs Are Recruited to Sites of Viral Replication on Membranes One of the most important trafficking pathways in the cell is the sorting of cargo once Publisher’s Note: MDPI stays neutral it has been internalized at the plasma membrane [1]. Cargo destined for degradation is with regard to jurisdictional claims in typically modified with a small protein tag known as ubiquitin, a process referred to as published maps and institutional affil- ubiquitylation, and is compartmentalized within an internal vesicle where it will become iations. part of the multivesicular body (MVB) on its way to the late endosome [2,3]. To ensure cargo has been compartmentalized during MVB biogenesis, the endosomal sorting complex required for transport (ESCRT) is recruited to the cargo by virtue of the ubiquitylation signal and directs cargo sorting [2,4]. The ubiquitin moiety from the cargo is detected Copyright: © 2021 by the authors. by the ESCRT-I component TSG101 as well as the ESCRT-associated protein ALIX [5,6]. Licensee MDPI, Basel, Switzerland. Once the cargo has been recognized, ESCRT-I can direct the sealing of the membrane This article is an open access article compartment through sequential interactions with ESCRT-II and ESCRT-III, while ALIX can distributed under the terms and recruit ESCRT-III directly (Figure1)[ 7]. ESCRT-III recruitment is temporally and spatially conditions of the Creative Commons dynamic within the cell where it forms filaments that mediate the scission and sealing Attribution (CC BY) license (https:// of a multitude of cellular membranes ranging from the nuclear envelope to the plasma creativecommons.org/licenses/by/ membrane and many membranes in between [8–12]. Typically responsible for orchestrating 4.0/). Viruses 2021, 13, 1138. https://doi.org/10.3390/v13061138 https://www.mdpi.com/journal/viruses Erratum 1 Erratum: Rose K.M. When in Need of an ESCRT: The Nature of 2 3 Viruses 2021Virus, 13, 1138 Assembly Sites Suggests Mechanistic Parallels between 2 of 13 Nuclear Virus Egress and Retroviral Budding. 2021, Vol. 13, 4 1138 the early events of membrane trafficking and scission in the cell, TSG101 and ALIX 5 are commonly hijacked by viruses to facilitate viral replication and dissemination, one of the 1,* 2 2 2 Kevin M. Rose , Stephaniemost J. Spada well studied, Vanessa of M. cases Hirsch coming , and from Fadila retroviruses Bouamr like the Human Immunodeficiency 6 Virus type 1 (HIV-1) [5,13]. In the case of HIV-1, the retroviral Gag protein encodes two late budding1Department domains of Molecular (L-domains). and Cell Biology, These California short Inst peptideitute formotifs Quantitative independently Biosciences, University recruit ofALIX (via7 California—Berkeley, Berkeley, CA 94720, USA 8 a LYPXnL2Laboratory motif) of Molecular and Microbiology, ESCRT-I (via National a PTAP Institute motif) of Allergy to and sites Infectious of viral Diseases, budding National and assembly 9 byInstitutes mimicking of Health, the Bethesda, peptide Rockville, signal MD found 20894,within USA; [email protected] the cognate cellular (S.J.S); partners of ALIX and10 [email protected] [5,13–15] (For (V.M.H.); review [email protected] see [16]). Additionally, (F.B.) retroviral Gag is ubiquitylated 11 by the* ubiquitinCorrespondence: ligase [email protected] NEDD4, and ubiquitin modification is essential for ESCRT-mediated 12 The authors wish to make the following erratum to this paper [1]: 13 budding [17]. Recruitment of ESCRTs therein ensures genome packaging and proper The published version of Figure 1 was missing labels. The correct Figure 1 is listed 14 maturation of the newly assembling retrovirus particle [18] (Figure2a). below: 15 16 FigureFigure 1. The 1. respective The respective roles ofroles ALIX of and ALIX ESCRT-I and ESCRT-I in the sorting in the ofso membranousrting of membranous cargo. Upon cargo. internalization, Upon internalization, ubiquitylated 17 ubiquitylated cargo is detected by ALIX (left) and ESCRT-I (right) for compartmentalization into intraluminal vesicles 18 cargo is detected by ALIX (left) and ESCRT-I (right) for compartmentalization into intraluminal vesicles that are destined that are destined for degradation via the late endosome. Both ALIX and ESCRT-I contain ubiquitin binding domains that 19 for degradationfacilitate this via first the latestep. endosome. Unlike ESCR BothT-I, ALIXALIX andpossesses ESCRT-I an containESCRT-III ubiquitin binding bindingdomain domainsthat allows that for facilitate the direct this first 20 step. Unlikerecruitment ESCRT-I, of ESCRT-III ALIX and possesses VPS4, the an mach ESCRT-IIIinery required binding for domain sealing of that cargo allows within for intraluminal the direct vesi recruitmentcles and abscising of ESCRT-III 21 and VPS4,these thevesicles machinery from the required endosomal for membrane. sealing of In cargo a similar within fashion, intraluminal the ESCRT-I vesicles component and abscising TSG101 binds these ubiquitylated vesicles from the 22 cargo, while the VPS28 component can recruit ESCRT-III through ESCRT-II which also binds ubiquitylated cargo as well 23 endosomal membrane. In a similar fashion, the ESCRT-I component TSG101 binds ubiquitylated cargo, while the VPS28 as phospho-inositol lipids. 24 component can recruit ESCRT-III through ESCRT-II which also binds ubiquitylated cargo as well as phospho-inositol lipids. The list of authors was incorrect and did not accurately reflect the contributions of 25 individualsDespite thethat conservationcontributed to th ofe L-Domainsoverall work. seenIt is changed in HIV-1 to: and host factors, there 26 are Kevin M. Rose 1,*, Stephanienotable J. Spada exceptions 2, Vanessa to M. the Hirsch consensus 2, and motifsFadila Bouamr commonly 2 associated with ESCRT recruitment, 27 namely in Simian Immunodeficiency Viruses (SIVs), or HIV-1-progenitor viruses, that encode divergent ALIX recruitment domains as determined by X-ray crystallography [19]. SIVs encode surprising species-dependent sequence variations in their ALIX recruitment Viruses 2021, 13, x. https://doi.org/10.3390/xxxxxdomains with virus isolated from rhesus macaque (SIVmac)www.mdpi.com/jou requiring arnal/viruses PYKEVTEDL motif, isolated from African green monkey (SIVagm) relying on a AYDPARKLL motif, and virus from sooty mangabey (SIVsmm) harboring a PYKEVTEDLLHLNSLF sequence for ALIX recruitment, each uniquely different from the consensus motif [20,21]. ALIX interactions with LYPXnL late domains are mediated by the central V domain of ALIX that has a hydrophobic cavity capable of accepting and stabilizing hydrophobic residues from an LYPXnL-containing binding partner [21]. ALIX recruitment by HIV-1 and SIVs with atypical motifs can be accomplished so long as the viruses encode a phenylalanine or tyrosine residue, with the proper flexibility to embed within the V domain of ALIX, independently of the immediate amino acid residues flanking the canonical LYPXnL motif
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