The Functionally Exchangeable L Domains in RSV and HIV‐1 Gag Direct Particle Release Through Pathways Linked by Tsg101

Medina, Gisselle N.; Zhang, Yongjun; Tang, Yi; Gottwein, Eva; Vana, Marcy L.; Bouamr, Fadila; Leis, Jonathan; Carter, Carol A.

doi:10.1111/j.1600-0854.2005.00323.x

Cited by 52 publications

(64 citation statements)

References 77 publications

(152 reference statements)

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“…Despite the similarities to ubiquitin, ISG15 does not promote degradation of substrates and may even target a distinct population of proteins (18). In the present study, we now show that ISG15 exhibited antiviral activity against ASLV VLP release, similar to its effects on HIV-1 VLPs, even though the two viruses use parallel pathways to release from cells (22,29). One mechanism proposed for inhibition of virus release by ISG15 is that it prevents ubiquitination of viral structural proteins, such as Gag (19,25).…”

Section: Discussionsupporting

confidence: 64%

“…All ASV Gag expression constructs were based on plasmid 2036, as previously described (14,22,29,45). The plasmid vector encoding ISG15 was a generous gift from Ronald Harty (University of Pennsylvania) and was previously described (23,24).…”

Section: Methodsmentioning

confidence: 99%

“…The dominant PTAP L-domain motif in the p6 region of HIV-1 Gag binds to the ESCRT-I protein, Tsg101 (10,46). The PY L-domain motif in the p2b region of ASLV Gag binds to a Nedd4-like E3 protein, which likely links ASLV Gag to the ESCRT-II machinery (14,22,29,45,48,49). It was reported that in the presence of ISG15 expression Tsg101 did not bind to HIV-1 Gag (24), and we have confirmed this observation (data not shown).…”

Section: Isg15 Overexpression Inhibited Aslv Vlp Release From 293/e Cmentioning

confidence: 99%

“…If ISG15 inhibition of HIV-1 Gag release resulted from the inability to recruit the ESCRT-I complex, we sought to determine whether covalently linking ESCRT proteins to the C terminus of HIV-1 Gag/P7L could bypass this inhibition. This construct with a point substitution in the PTAP sequence expresses a Gag protein with a budding defect (22). We previously described the capacity of the ESCRT-I protein, Vps37C, and the ESCRT-III protein, CHMP6, to complement the PTAP L-domain mutation when tethered to HIV-1 Gag/P7L (29).…”

Section: Isg15 Overexpression Inhibited Aslv Vlp Release From 293/e Cmentioning

confidence: 99%

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The Interferon-Induced Gene ISG15 Blocks Retrovirus Release from Cells Late in the Budding Process

Pincetic

Kuang

Seo

et al. 2010

J Virol

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The release of retroviruses from cells requires ubiquitination of Gag and recruitment of cellular proteins involved in endosome sorting, including the ESCRT-III proteins and the Vps4 ATPase. In response to infection, cells have evolved an interferon-induced mechanism to block virus replication through expression of the interferon-stimulated gene 15 (ISG15), a dimer homologue of ubiquitin, which interferes with ubiquitin pathways in cells. Previously, it has been reported that ISG15 expression inhibited the E3 ubiquitin ligase, Nedd4, and prevented association of the ESCRT-I protein Tsg101 with human immunodeficiency virus type 1 (HIV-1) Gag. The budding of avian sarcoma leukosis virus and HIV-1 Gag virus-like particles containing L-domain mutations can be rescued by fusion to ESCRT proteins, which cause entry into the budding pathway beyond these early steps. The release of these fusions from cells was susceptible to inhibition by ISG15, indicating that there was a block late in the budding process. We now demonstrate that the Vps4 protein does not associate with the avian sarcoma leukosis virus or the HIV-1 budding complexes when ISG15 is expressed. This is caused by a loss in interaction between Vps4 with its coactivator protein LIP5 needed to promote the formation of the ESCRT-III-Vps4 double-hexamer complex required for membrane scission and virus release. The inability of LIP5 to interact with Vps4 is the probable result of ISG15 conjugation to the ESCRT-III protein, CHMP5, which regulates the availability of LIP5. Thus, there appear to be multiple levels of ISG15-induced inhibition acting at different stages of the virus release process.

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Section: Discussionsupporting

confidence: 64%

Section: Methodsmentioning

confidence: 99%

Section: Isg15 Overexpression Inhibited Aslv Vlp Release From 293/e Cmentioning

confidence: 99%

Section: Isg15 Overexpression Inhibited Aslv Vlp Release From 293/e Cmentioning

confidence: 99%

See 2 more Smart Citations

The Interferon-Induced Gene ISG15 Blocks Retrovirus Release from Cells Late in the Budding Process

Pincetic

Kuang

Seo

et al. 2010

J Virol

Self Cite

133

140

View full text Add to dashboard Cite

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“…PPxYcontaining viral proteins might be concentrated at sites of viral assembly through their direct interaction with Nedd4 proteins. Indeed, one member of the Nedd4 family stably associates with Tsg101, a subunit of ESCRT-I (Medina et al, 2005), indicating a physical link exists between the E3 Ub ligase and core MVB sorting components. Recently, Rsp5 was found to bind directly to Hse1, a subunit of the ESCRT-0 complex (Ren et al, 2006), which might explain how Sna3 bound to Rsp5 gains accesses the class E Vps/ESCRT MVB sorting machinery.…”

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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Emerging roles of HECT‐type E3 ubiquitin ligases in autophagy regulation

et al. 2019

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Autophagy is a conserved self‐eating process that delivers cytoplasmic material to the lysosome to allow degradation of intracellular components, including soluble, unfolded and aggregated proteins, damaged organelles, and invading microorganisms. Autophagy provides a homeostatic control mechanism and is essential for balancing sources of energy in response to nutrient stress. Autophagic dysfunction or dysregulation has been implicated in several human pathologies, including cancer and neurodegeneration, and its modulation has substantial potential as a therapeutic strategy. Given the relevant clinical and therapeutic implications of autophagy, there is emerging intense interest in the identification of the key factors regulating the components of the autophagic machinery. Various post‐translational modifications, including ubiquitylation, have been implicated in autophagy control. The list of the E3 ubiquitin protein ligases involved in the regulation of several steps of the autophagic process is continuously growing. In this review, we will focus on recent advances in the understanding of the role of the homologous to the E6AP carboxyl terminus‐type E3 ubiquitin ligases in autophagy control.

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The Functionally Exchangeable L Domains in RSV and HIV‐1 Gag Direct Particle Release Through Pathways Linked by Tsg101

Cited by 52 publications

References 77 publications

The Interferon-Induced Gene ISG15 Blocks Retrovirus Release from Cells Late in the Budding Process

The Interferon-Induced Gene ISG15 Blocks Retrovirus Release from Cells Late in the Budding Process

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

Emerging roles of HECT‐type E3 ubiquitin ligases in autophagy regulation

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