Role of Nedd4 and Ubiquitination of Rous Sarcoma Virus Gag in Budding of Virus-Like Particles from Cells

Vana, Marcy L.; Tang, Yi; Chen, Aiping; Medina, Gisselle N.; Carter, Carol; Leis, Jonathan

doi:10.1128/jvi.78.24.13943-13953.2004

Cited by 59 publications

(78 citation statements)

References 26 publications

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“…PPxY or PxY motifs are common binding sites for WW domains in Rsp5 (Chang et al, 2000) and in the Nedd4 family of HECT domain E3 Ub ligases in mammalian cells, which are homologues of Rsp5 (Ingham et al, 2004). Notably, several types of enveloped viruses encode structural proteins containing PPxY motifs that bind Nedd4 and bud from infected cells by a process that is both topologically equivalent to MVB vesicle budding and is dependent on the functions of class E Vps proteins (Harty et al, 2000;Bouamr et al, 2003;Gottwein et al, 2003;Martin-Serrano et al, 2004;Vana et al, 2004;SeguraMorales et al, 2005; reviewed in Morita and Sundquist, 2004). Like Rsp5, Nedd4 proteins function in ubiquitination of cargoes sorted into the MVB pathway (Staub et al, 1997;Marchese et al, 2003), but whether ubiquitination of viral proteins by Nedd4 is directly required for packaging of viral particles is unclear (Morita and Sundquist, 2004).…”

Section: Discussionmentioning

confidence: 99%

Direct Binding to Rsp5 Mediates Ubiquitin-independent Sorting of Sna3 via the Multivesicular Body Pathway

McNatt

McKittrick

West

et al. 2007

MBoC

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The sorting of most integral membrane proteins into the lumenal vesicles of multivesicular bodies (MVBs) is dependent on the attachment of ubiquitin (Ub) to their cytosolic domains. However, Ub is not required for sorting of Sna3, an MVB vesicle cargo protein in yeast. We show that Sna3 circumvents Ub-mediated recognition by interacting directly with Rsp5, an E3 Ub ligase that catalyzes monoubiquitination of MVB vesicle cargoes. The PPAY motif in the C-terminal cytosolic domain of Sna3 binds the WW domains in Rsp5, and Sna3 is polyubiquitinated as a consequence of this association. However, Ub does not appear to be required for transport of Sna3 via the MVB pathway because its sorting occurs under conditions in which its ubiquitination is impaired. Consistent with Ub-independent function of the MVB pathway, we show by electron microscopy that the formation of MVB vesicles does not require Rsp5 E3 ligase activity. However, cells expressing a catalytically disabled form of Rsp5 have a greater frequency of smaller MVB vesicles compared with the relatively broad distribution of vesicles seen in MVBs of wild-type cells, suggesting that the formation of MVB vesicles is influenced by Rsp5-mediated ubiquitination. INTRODUCTIONMultivesicular bodies (MVBs) are late endosomes containing lumenal vesicles that are formed by invagination of the endosomal membrane. The lumenal MVB vesicles are delivered into the hydrolytic interior of the lysosome upon fusion of the limiting MVB membrane with the lysosomal membrane (van Deurs et al., 1995;Futter et al., 1996;Mullock et al., 1998). Many cell-surface receptors that undergo down-regulation from the plasma membrane are sorted into MVB vesicles en route to being degraded in the lysosome, including members of the receptor tyrosine kinase family in metazoans and G protein-coupled receptors in the budding yeast Saccharomyces cerevisiae. In yeast, many biosynthetic proteins are also sorted into MVB vesicles during their transport from the Golgi to the vacuole, the functional equivalent of the lysosome (reviewed in Hicke and Dunn, 2003).Most integral membrane proteins require the attachment of a single ubiquitin (Ub) to their cytosolic domains in order to be sorted into the MVB pathway (Katzmann et al., 2001;Reggiori and Pelham, 2001;Urbanowski and Piper, 2001). Sorting of monoubiquitinated MVB cargoes is mediated by a highly conserved machinery comprised of class E Vps proteins, many of which assemble into distinct endosomal sorting complexes required for transport (ESCRTs) that contain Ub-binding domains (reviewed in Hurley and Emr, 2006). In addition to Ub-mediated cargo recognition, class E Vps proteins are generally required for MVB vesicle budding because cells in which class E Vps proteins are disrupted contain malformed late endosomes that lack lumenal vesicles (Rieder et al., 1996;Odorizzi et al., 1998;Doyotte et al., 2005).The class E Vps/ESCRT machinery is also required for the budding of many nonlytic enveloped viruses from infected host cells, which is topologically equival...

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Section: Discussionmentioning

confidence: 99%

Direct Binding to Rsp5 Mediates Ubiquitin-independent Sorting of Sna3 via the Multivesicular Body Pathway

McNatt

McKittrick

West

et al. 2007

MBoC

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“…We chose to further examine Nedd4, because it is the prototypical member of the Nedd4 family of ubiquitin ligases and has been shown to be a cofactor for PPXY motif (PY motif)-dependent viral budding (6,23,36,60,71,80). Unfortunately, other candidate Nedd4 family proteins could not be tested, either because antibodies were not available or because they were not detected in Vero cell lysates with commercially available antibodies.…”

Section: Several Nedd4 Family Ubiquitin Ligases Interact With Ul56mentioning

confidence: 99%

“…Nedd4 regulates viral budding of Ebola virus (23,80), human T-cell leukemia virus type 1 (6,60), and Rous sarcoma virus (36,71). In addition to these viruses, many enveloped RNA and DNA viruses exploit the multivesicular body (MVB) machinery for budding, such as retroviruses (21,56,74,79,81), rhabdoviruses (12), other filoviruses (38), arenaviruses (54,64), paramyxoviruses (59,62), hepatitis B virus (44,76), HSV (8,13), and probably orthomyxoviruses and human herpes virus type 6 (47).…”

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confidence: 99%

“…Further analysis revealed that Nedd4 was expressed at various levels in several embryonic and adult tissues (42). Nedd4 is the prototypical member of the Nedd4 ubiquitin ligase family and regulates diverse cellular processes including signal transduction (which is involved in cancer development [10,49,73,75]), protein trafficking (52, 63), and viral budding (6,23,36,60,71,80).…”

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confidence: 99%

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Herpes Simplex Virus Type 2 UL56 Interacts with the Ubiquitin Ligase Nedd4 and Increases Its Ubiquitination

Ushijima

Koshizuka

Goshima

et al. 2008

J Virol

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The herpes simplex virus UL56 gene is conserved among most members of the Alphaherpesvirinae family and plays a critical role in viral pathogenicity in vivo. The HSV-2 UL56 protein (UL56) is a C-terminally anchored type II membrane protein that is predicted to be inserted into the virion envelope, leaving its N-terminal domain in the tegument. UL56 interacts with KIF1A and UL11. Here we report that UL56 also interacts with the ubiquitin ligase Nedd4 and increases its ubiquitination. Nedd4 was identified as a UL56-interacting protein by a yeast two-hybrid screen. UL56 bound to Nedd4 via its PY motifs. Nedd4 was phosphorylated and degraded in wild-type HSV-2-infected cells but not in cells infected with a UL56-deficient mutant. Ubiquitination assays revealed that UL56 increased ubiquitinated Nedd4, which was actively degraded in infected cells. UL56 also caused a decrease in Nedd4 protein levels and the increased ubiquitination in cotransfected cells. However, UL56 itself was not ubiquitinated, despite its interaction with Nedd4. Based on these findings, we propose that UL56 regulates Nedd4 in HSV-2-infected cells, although deletion of UL56 had no apparent effect on viral growth in vitro.Herpes simplex virus (HSV) is a large, enveloped DNA virus with a genome possessing at least 74 different genes (19,46). Although approximately half of the HSV genes are not essential for replication in vitro, all of these accessory gene products are predicted to play indispensable roles in viral replication and dissemination in vivo (57).The HSV UL56 gene is an accessory gene that most members of the Alphaherpesvirinae family possess homologs for (except bovine herpes virus-1 and -5) (1,17,19,22,29,34,37,46,53,(65)(66)(67)(68)(69)(70); M. Schwyzer, V. Paces, G. J. Letchworth, V. Misra, H. J. Buhk, D. E. Lowery, C. Simard, L. J. Bello, E. Thiry, and C. Vlcek, 1995, complete DNA sequence of bovine herpesvirus 1. GenBank database [http://www.ncbi.nlm.nih.gov/Genbank/index .html] accession number NC_001847) and has been shown to play an important role in HSV type 1 (HSV-1) pathogenicity in vivo. UL56-deficient HSV-1 mutants are substantially less neuroinvasive (4, 58), although little is known molecularly about how this attenuation occurs. HSV-2 UL56 is a 235-amino-acid, C-terminally anchored, type II membrane protein (39) that is predicted to be inserted into the viral envelope so that the N-terminal domain is located in the virion tegument. In this topology, UL56 is predicted to have a 216-amino-acid cytoplasmic domain. UL56 associates with the neuron-specific kinesin KIF1A (41) and the HSV-2 protein UL11 (40). KIF1A is involved in the axonal transport of synaptic vesicle precursors (51), and its association with UL56 suggests that UL56 may affect vesicular transport in infected neurons. UL11 is a tegument protein that is involved in the envelopment and egress of viral nucleocapsids (3) and has dynamic membrane-trafficking properties (45). UL56 may specifically promote UL11 function in virion envelopment and egress in infected neur...

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“…The YPXL and LXXLF motifs bind to AIP-1/Alix, which acts downstream of Tsg101 and appears to bridge ESCRT-I and ESCRT-III complexes (42,66,73). The third motif, PPXY, plays a role in recruiting host ubiquitin ligases (7,8,17,34,38,40,54,70,73,79,80). Although it is clear that the cellular ubiquitination machinery is important for the budding of many animal viruses, current knowledge about the exact targets of the ubiquitin ligases and their interactions with other components of the budding machinery is still very limited (7,41,47,49,53).…”

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confidence: 99%

Nonstructural Protein 3 of Bluetongue Virus Assists Virus Release by Recruiting ESCRT-I Protein Tsg101

Wirblich

Bhattacharya

Roy

2006

J Virol

117

126

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The release of Bluetongue virus (BTV) and other members of the Orbivirus genus from infected host cells occurs predominantly by cell lysis, and in some cases, by budding from the plasma membrane. Two nonstructural proteins, NS3 and NS3A, have been implicated in this process. Here we show that both proteins bind to human Tsg101 and its ortholog from Drosophila melanogaster with similar strengths in vitro. This interaction is mediated by a conserved PSAP motif in NS3 and appears to play a role in virus release. The depletion of Tsg101 with small interfering RNA inhibits the release of BTV and African horse sickness virus, a related orbivirus, from HeLa cells up to fivefold and threefold, respectively. Like most other viral proteins which recruit Tsg101, NS3 also harbors a PPXY late-domain motif that allows NS3 to bind NEDD4-like ubiquitin ligases in vitro. However, the late-domain motifs in NS3 do not function as effectively in facilitating the release of mini Gag virus-like particles from 293T cells as the late domains from human immunodeficiency virus type 1, human T-cell leukemia virus, and Ebola virus. A mutagenesis study showed that the arginine residue in the PPRY motif is responsible for the low activity of the NS3 late-domain motifs. Our data suggest that the BTV late-domain motifs either recruit an antagonist that interferes with budding or fail to recruit an agonist which is different from NEDD4.

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Role of Nedd4 and Ubiquitination of Rous Sarcoma Virus Gag in Budding of Virus-Like Particles from Cells

Cited by 59 publications

References 26 publications

Direct Binding to Rsp5 Mediates Ubiquitin-independent Sorting of Sna3 via the Multivesicular Body Pathway

Direct Binding to Rsp5 Mediates Ubiquitin-independent Sorting of Sna3 via the Multivesicular Body Pathway

Herpes Simplex Virus Type 2 UL56 Interacts with the Ubiquitin Ligase Nedd4 and Increases Its Ubiquitination

Nonstructural Protein 3 of Bluetongue Virus Assists Virus Release by Recruiting ESCRT-I Protein Tsg101

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