Abstract
BackgroundThe ESCRT (endosomal sorting complex required for transport) machinery functions to sort cellular receptors into the lumen of the multivesicular body (MVB) prior to lysosomal degradation. ESCRT components can also be recruited by enveloped viruses to sites of viral assembly where they have been proposed to mediate viral egress. For example, HIV-1 budding is dependent on Gag-mediated recruitment of the cellular ESCRTs-I, -III, AIP1/Alix and Vps4 proteins. Viral recruitment of ESCRT proteins could therefore impact on host cell processes such as receptor downregulation.ResultsHere we show that downregulation of the HIV-1 co-receptor, CXCR4, by its ligand SDF-1, is ESCRT-I dependent. Expression of HIV-1 Gag attenuated downregulation of CXCR4, resulting in accumulation of undegraded receptors within intracellular compartments. The effect of Gag was dependent on an ESCRT-I interacting motif within the C-terminal p6 region of Gag. In contrast, PMA-induced downregulation of the HIV-1 receptor CD4 was independent of ESCRT-I and Vps4; HIV-1 Gag had no effect on this process.ConclusionThese results establish that the HIV-1 receptor, CD4, and co-receptor, CXCR4 are differentially regulated by ESCRT proteins. HIV-1 Gag selectively modulates protein sorting at the MVB, interfering with ESCRT-I dependent but not ESCRT-I independent processes.
Highlights
The endosomal sorting complex required for transport (ESCRT) machinery functions to sort cellular receptors into the lumen of the multivesicular body (MVB) prior to lysosomal degradation
This process is initiated by the ubiquitin-binding protein, Hrs, which recruits the endosomal sorting complex required for transport (ESCRT)-I to endosomal membranes by directly interacting with the ESCRT-I component, TSG101 (Tumor Susceptibility Gene 101) [3]
SDF-1 induced CXCR4 downregulation is ESCRT-I dependent Previous studies have established that SDF-1 induces internalization, endosomal trafficking and lysosomal degradation of CXCR4 and HA-tagged CXCR4 in a variety of cell types [19,20,30]
Summary
The ESCRT (endosomal sorting complex required for transport) machinery functions to sort cellular receptors into the lumen of the multivesicular body (MVB) prior to lysosomal degradation. Internalized receptors are sorted into endosomal membrane invaginations, which pinch off to form intralumenal vesicles within the MVB This process is initiated by the ubiquitin-binding protein, Hrs, which recruits the endosomal sorting complex required for transport (ESCRT)-I to endosomal membranes by directly interacting with the ESCRT-I component, TSG101 (Tumor Susceptibility Gene 101) [3]. Following ESCRT-I recruitment, ESCRTs-II and III are sequentially localized to the endosomal membrane [1]. These complexes bind ubiquitylated receptors and are required for receptor sorting into the lumen of the MVB. The AAA type ATPase Vps facilitates the disassembly of the ESCRT complexes prior to membrane fission, thereby ensuring that these complexes are available for further rounds of protein sorting [4]
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