Differential control of CXCR4 and CD4 downregulation by HIV-1 Gag

Article (PDF Available)inVirology Journal 5(1):23 · February 2008with16 Reads
DOI: 10.1186/1743-422X-5-23 · Source: PubMed
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. 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. Here 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. These 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.

Full-text (PDF)

Available from: PubMed Central · License: CC BY
  • [Show abstract] [Hide abstract] ABSTRACT: G protein-coupled receptor (GPCR) sorting into the degradative pathway is important for limiting the duration and magnitude of signaling. Agonist activation of the GPCR CXCR4 induces its rapid ubiquitination and sorting to lysosomes via the endosomal sorting complex required for transport (ESCRT) pathway. We recently reported that ESCRT-0 ubiquitination is linked to the efficiency with which CXCR4 is sorted for lysosomal degradation, however mechanistic insight is lacking. Here, we define a novel role for the RING-domain E3 ubiquitin ligase Deltex-3-like (DTX3L) in regulating CXCR4 sorting from endosomes to lysosomes. We show that DTX3L localizes to early endosomes upon CXCR4 activation and interacts directly with and inhibits the activity of the E3 ubiquitin ligase atrophin-1 interacting protein 4 (AIP4). This serves to limit the extent to which ESCRT-0 is ubiquitinated and is able to sort CXCR4 for lysosomal degradation. Therefore we have defined a novel role for DTX3L in GPCR endosomal sorting and reveal an unprecedented link between two distinct E3 ubiquitin ligases to control the activity of the ESCRT machinery.
    Article · Apr 2014
  • [Show abstract] [Hide abstract] ABSTRACT: G protein-coupled receptor (GPCR) signaling mediates many cellular functions, including cell survival, proliferation and cell motility. Many of these processes are mediated by GPCR promoted activation of Akt signaling by mammalian target of rapamycin complex 2 (mTORC2) and the phosphatidyl inositol 3-kinase (PI3K)/phosphoinositide-dependent kinase (PDK1) pathway. However, the molecular mechanisms by which GPCRs govern Akt activation by these kinases remains poorly understood. Here we show that the ESCRT (Endosomal Sorting Complex Required for Transport) pathway mediates Akt signaling promoted by the chemokine receptor CXCR4. Pharmacological inhibition of heterotrimeric G protein Gαi or PI3K signaling and siRNA targeting ESCRTs blocks CXCR4 promoted degradation of DEPTOR, an endogenous antagonist of mTORC2 activity. Depletion of ESCRTs by siRNA leads to increased levels of DEPTOR and attenuated CXCR4 promoted Akt activation and signaling, consistent with decreased mTORC2 activity. In addition, ESCRTs likely have a broad role in Akt signaling because ESCRT depletion also attenuates receptor tyrosine kinase (RTK) promoted Akt activation and signaling. Our data reveal a novel role for the ESCRT pathway in promoting intracellular signaling, which may begin to identify the signal transduction pathways that are important in the physiological roles of ESCRTs and Akt. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
    Article · Jan 2015
  • [Show abstract] [Hide abstract] ABSTRACT: G protein-coupled receptor (GPCR)-promoted signaling mediates cellular responses to a variety of stimuli involved in diverse physiological processes. In addition, GPCRs are also the largest class of target for many drugs used to treat a variety of diseases. Despite the role of GPCR signaling in health and disease, the molecular mechanisms governing GPCR signaling remain poorly understanding. Classically, GPCR signaling is tightly regulated by GPCR kinases and β-arrestins, which act in a concerted fashion to govern GPCR desensitization and also GPCR trafficking. Ubiquitination has now emerged as an important posttranslational modification that has multiple roles, either directly or indirectly, in governing GPCR trafficking. Recent studies have revealed a mechanistic link between GPCR phosphorylation, β-arrestins, and ubiquitination. Here, we review recent developments in our understanding of how ubiquitin regulates GPCR trafficking within the endocytic pathway. © 2015 Elsevier Inc. All rights reserved.
    Article · Dec 2015

Recommended publications

Discover more