Abstract
SummaryThe endosomal sorting complexes required for transport (ESCRTs) facilitate endosomal sorting of ubiquitinated cargo, MVB biogenesis, late stages of cytokinesis, and retroviral budding. Here we show that ubiquitin associated protein 1 (UBAP1), a subunit of human ESCRT-I, coassembles in a stable 1:1:1:1 complex with Vps23/TSG101, VPS28, and VPS37. The X-ray crystal structure of the C-terminal region of UBAP1 reveals a domain that we describe as a solenoid of overlapping UBAs (SOUBA). NMR analysis shows that each of the three rigidly arranged overlapping UBAs making up the SOUBA interact with ubiquitin. We demonstrate that UBAP1-containing ESCRT-I is essential for degradation of antiviral cell-surface proteins, such as tetherin (BST-2/CD317), by viral countermeasures, namely, the HIV-1 accessory protein Vpu and the Kaposi sarcoma-associated herpesvirus (KSHV) ubiquitin ligase K5.
Highlights
The endosomal sorting complex required for transport (ESCRT) machinery facilitates the lysosomal degradation of ubiquitinated cell surface receptors (Hurley and Stenmark, 2011; Katzmann et al, 2001)
We show that ubiquitin associated protein 1 (UBAP1) is required for ubiquitin-dependent degradation of the antiviral protein tetherin triggered by the viral countermeasures HIV-I protein Vpu and Kaposi sarcoma-associated herpesvirus (KSHV) viral protein K5
Endogenous UBAP1 was efficiently copurified with TSG101 and VPS37A from a cell line stably expressing TSG101 with a One-Strep tag (OSHATSG101) (Figure 1C)
Summary
The endosomal sorting complex required for transport (ESCRT) machinery facilitates the lysosomal degradation of ubiquitinated cell surface receptors (Hurley and Stenmark, 2011; Katzmann et al, 2001). The ability of the ESCRTs to mediate scission of a thin membranous stalk is exploited by several enveloped viruses such as HIV-1 to facilitate their release from infected cells (Baumgartel et al, 2011; Jouvenet et al, 2011; Martin-Serrano and Neil, 2011; Morita and Sundquist, 2004; Morita et al, 2011; Weissenhorn and Gottlinger, 2011). Additional roles of ESCRT-I in viral pathogenesis include its cooption by gamma-herpesviruses (Nathan and Lehner, 2009) and HIV for the degradation of various antiviral cell-surface proteins such as tetherin (BST-2/CD317) (reviewed in Martin-Serrano and Neil, 2011). Kaposi sarcoma-associated herpesvirus (KSHV) encodes K5, a membrane-bound E3 ubiquitin ligase that results in a similar effect (Bartee et al, 2006; Mansouri et al, 2009; Pardieu et al, 2010)
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