Identification of human VPS37C, a component of ESCRT-I important for viral budding

Aaron Diamond AIDS Research Center and the Rockefeller University, New York, New York 10016, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 02/2005; 280(1):628-36. DOI: 10.1074/jbc.M410384200
Source: PubMed


Endosomal sorting complex required for transport-I (ESCRT-I) is one of three defined protein complexes in the class E vacuolar protein sorting (VPS) pathway required for the sorting of ubiquitinated transmembrane proteins into internal vesicles of multivesicular bodies. In yeast, ESCRT-I is composed of three proteins, VSP23, VPS28, and VPS37, whereas in mammals only Tsg101(VPS23) and VPS28 were originally identified as ESCRT-I components. Using yeast two-hybrid screens, we identified one of a family of human proteins (VPS37C) as a Tsg101-binding protein. VPS37C can form a ternary complex with Tsg101 and VPS28 by binding to a domain situated toward the carboxyl terminus of Tsg101 and binds to another class E VPS factor, namely Hrs. In addition, VPS37C is recruited to aberrant endosomes induced by overexpression of Tsg101, Hrs, or dominant negative form of the class E VPS ATPase, VPS4. Enveloped viruses that encode PTAP motifs to facilitate budding exploit ESCRT-I as an interface with the class E VPS pathway, and accordingly, VPS37C is recruited to the plasma membrane along with Tsg101 by human immunodeficiency virus, type 1 (HIV-1) Gag. Moreover, direct fusion of VPS37C to HIV-1 Gag obviates the requirement for a PTAP motif to induce virion release. Depletion of VPS37C from cells does not inhibit murine leukemia virus budding, which is not mediated by ESCRT-I, however, if murine leukemia virus budding is engineered to be ESCRT-I-dependent, then it is inhibited by VPS37C depletion, and this inhibition is accentuated if VPS37B is simultaneously depleted. Thus, this study identifies VPS37C as a functional component of mammalian ESCRT-I.

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    • "The interaction with ESCRT-0 occurs through the N-terminus of Vps23p whereas the binding to ESCRT-II is mediated by the C-terminal region of Vps28 (Katzmann et al. 2003; Kostelansky et al. 2006). The structural organization of ESCRT-I is thought to be conserved between yeast and metazoans, although mammals present a much greater diversity of ESCRT-I subunits, including four isoforms of VPS37 (VPS37A–D) and two of MVB12 (MVB12A and B) (Bache et al. 2004; Stuchell et al. 2004; Eastman et al. 2005; Morita et al. 2007). Yeast ESCRT-I binds ubiquitin through an N-terminal UEV (ubiquitin E2 variant) domain in Vps23p and the C-terminal domain in Mvb12p, both contributing to the ability of ESCRT-I to sort ubiquitinated cargo proteins in MVBs. "
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    DESCRIPTION: ESCRT �-Plant endosomes �-Multivesicular bodies
    Full-text · Research · Nov 2015
    • "This might point to the presence of additional ESCRT-I complexes acting alongside that containing UBAP1, though it is also possible that a TSG101–VPS28–VPS37A complex lacking UBAP1 retains some sorting activity. The documented interaction between VPS37C and the ESCRT-0 component, hepatocyte growth factor receptor substrate (Hrs) (Eastman et al., 2005), is also consistent with the possibility that other ESCRT-I complexes have some endosomal function. By analogy, ESCRTs perform two roles during cytokinesis; they drive membrane scission but also promote microtubule disassembly by recruiting the microtubule severing protein, spastin (Caballe and Martin-Serrano, 2011; Yang et al., 2008). "
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    ABSTRACT: ESCRT-I is essential for the multivesicular body (MVB) sorting of ubiquitinated cargo such as epidermal growth factor receptor, as well as for divergent cellular functions such as cell division and retroviral budding. ESCRT-I has four subunits; TSG101, VPS28, VPS37 and MVB12. There are several members of VPS37 and MVB12 families in mammalian cells, and their differential incorporation into ESCRT-I could provide function-specific variants of the complex. However, it remains unclear whether these different forms of VPS37 and MVB12 combine randomly or generate selective pairings within ESCRT-I, and what the mechanistic basis for such pairing would be. Here we show that the incorporation into ESCRT-I of two MVB12 members, UBAP1 and MVB12A, is highly selective with respect to their VPS37 partners. We map the selective assembly of UBAP1/VPS37A to the core ESCRT-I binding domain of VPS37A. In contrast, selective integration of UBAP1 requires both the minimal ESCRT-I binding region and a neighbouring predicted helix. The biochemical specificity in ESCRT-I assembly is matched by functional specialisation, since siRNA-mediated depletion of UBAP1, but not MVB12A or MVB12B, disrupts ubiquitin-dependent sorting at the MVB.
    No preview · Article · Nov 2013 · Journal of Cell Science
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    • "ESCRT-I includes TSG101 [50,82], VPS28 [83-85], one copy of one of the four versions of VPS37 (A-D) [86-88] and one of the two versions of MVB12 (A&B) [84,89,90] in a stoichiometry of 1:1:1:1 [84,89,91]. The budding of HIV requires the intact ESCRT-I, although the involvement of VPS37A and VPS37D in this process have not been reported. "
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    ABSTRACT: The late Nobel Laureate Sir Peter Medawar once memorably described viruses as 'bad news wrapped in protein'. Virus assembly in HIV is a remarkably well coordinated process in which the virus achieves extracellular budding using primarily intracellular budding machinery and also the unusual phenomenon of export from the cell of an RNA. Recruitment of the ESCRT system by HIV is one of the best documented examples of the comprehensive way in which a virus hijacks a normal cellular process. This review is a summary of our current understanding of the budding process of HIV, from genomic RNA capture through budding and on to viral maturation, but centering on the proteins of the ESCRT pathway and highlighting some recent advances in our understanding of the cellular components involved and the complex interplay between the Gag protein and the genomic RNA.
    Full-text · Article · Jan 2013 · Retrovirology
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