Abstract
The Endosomal Sorting Complexes Required for Transport (ESCRT) machinery, a highly conserved set of four hetero-oligomeric protein complexes, is required for multivesicular body formation, sorting ubiquitinylated membrane proteins for lysosomal degradation, cytokinesis and the final stages of assembly of a number of enveloped viruses, including the human immunodeficiency viruses. Here, we show an additional role for the ESCRT machinery in HIV-1 release. BST-2/tetherin is a restriction factor that impedes HIV release by tethering mature virus particles to the plasma membrane. We found that HRS, a key component of the ESCRT-0 complex, promotes efficient release of HIV-1 and that siRNA-mediated HRS depletion induces a BST-2/tetherin phenotype. This activity is related to the ability of the HIV-1 Vpu protein to down-regulate BST-2/tetherin. We found that BST-2/tetherin undergoes constitutive ESCRT-dependent sorting for lysosomal degradation and that this degradation is enhanced by Vpu expression. We demonstrate that Vpu-mediated BST-2/tetherin down-modulation and degradation require HRS (ESCRT-0) function and that knock down of HRS increases cellular levels of BST-2/tetherin and restricts virus release. Furthermore, HRS co-precipitates with Vpu and BST-2. Our results provide further insight into the mechanism by which Vpu counteracts BST-2/tetherin and promotes HIV-1 dissemination, and they highlight an additional role for the ESCRT machinery in virus release.
Highlights
The assembly and release of HIV-1 particles requires a highly orchestrated series of interactions between proteins encoded by the virus and key cellular components, including elements of the cellular membrane trafficking apparatus and the ESCRT (Endosomal Sorting Complexes Required for Transport) machinery [1,2,3]
HRS is required for efficient HIV-1 release To investigate the role of the ESCRT-0 component HRS on HIV-1 replication, we depleted HRS in HeLa cells and analysed the effect on HIV-1 propagation
Studies of the mechanism through which HIV-1 particles are assembled and released from infected cells have revealed a major role for the ESCRT machinery
Summary
The assembly and release of HIV-1 particles requires a highly orchestrated series of interactions between proteins encoded by the virus and key cellular components, including elements of the cellular membrane trafficking apparatus and the ESCRT (Endosomal Sorting Complexes Required for Transport) machinery [1,2,3]. The budding of HIV-1 particles at the plasma membrane resembles the budding of intralumenal vesicles into MVBs. the HIV-1 Gag protein, the major structural protein of the virus, can recruit the ESCRT-I and ESCRT-III complexes through its C-terminal p6 domain (so called ‘‘late domain’’) to mediate release of budding virions [5,6,7,8]. HRS was recently identified in a genome-wide siRNA screen for host cell factors involved in HIV-1 replication, suggesting an active role for ESCRT-0 [10]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
