Structural basis of HIV-1 Vpu-mediated BST2 antagonism via hijacking of the clathrin adaptor protein complex 1

Jia, Xiaofei; Weber, Elizabeth; Tokarev, Andrey; Lewinski, Mary K.; Rizk, Maryan; Suarez, Marissa; Xiong, Yong

doi:10.7554/elife.02362

Cited by 90 publications

(151 citation statements)

References 95 publications

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“…Another possibility is that the C-terminal membrane attachment correctly orients the cytoplasmic domain of Vpu such that it can interact with a cellular peripheral membrane or cytoskeletal protein, and this connection ultimately provides the movement of BST2 relative to viral assembly sites. Such a co-factor might, for example, be a clathrin adaptor, an hypothesis consistent with the role reported for the EXXXLV 64 adaptor protein binding sequence in the displacement effect (16,42). In either case, Vpu would presumably need to interact with BST2 at assembly sites initially, and then move together with BST2 away from those sites.…”

Section: Discussionmentioning

confidence: 55%

Membrane Anchoring by a C-terminal Tryptophan Enables HIV-1 Vpu to Displace Bone Marrow Stromal Antigen 2 (BST2) from Sites of Viral Assembly

Lewinski

Jafari²,

Zhang

et al. 2015

Journal of Biological Chemistry

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Background: HIV-1 Vpu displaces bone marrow stromal antigen 2 (BST2) from sites of viral assembly. Results: A tryptophan residue near the C terminus of Vpu is required for this activity and interacts with the lipid bilayer. Conclusion: Interaction of the C terminus of Vpu with the lipid bilayer helps HIV-1 escape restriction by BST2. Significance: The topology of the cytoplasmic domain of Vpu with respect to the lipid bilayer is a key aspect of BST2 antagonism.

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Section: Discussionmentioning

confidence: 55%

Membrane Anchoring by a C-terminal Tryptophan Enables HIV-1 Vpu to Displace Bone Marrow Stromal Antigen 2 (BST2) from Sites of Viral Assembly

Lewinski

Jafari²,

Zhang

et al. 2015

Journal of Biological Chemistry

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“…Bst2 has also been shown to activate the NF-B pathway, presumably further amplifying cellular stress signals (17). While the functional roles of Bst2 in uninfected cells are just emerging, it is clear that many viruses encode proteins that subvert Bst2's antiviral activities, often by altering clathrin-mediated endocytic pathways (18)(19)(20). To date, studies aimed at understanding Bst2's role in preventing viral infection have been limited Citation Holmgren AM, Miller KD, Cavanaugh SE, Rall GF.…”

mentioning

confidence: 99%

Bst2/Tetherin Is Induced in Neurons by Type I Interferon and Viral Infection but Is Dispensable for Protection against Neurotropic Viral Challenge

Holmgren

Miller

Cavanaugh

et al. 2015

J Virol

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In permissive mouse central nervous system (CNS) neurons, measles virus (MV) spreads in the absence of hallmark viral budding or neuronal death, with transmission occurring efficiently and exclusively via the synapse. MV infection also initiates a robust type I interferon (IFN) response, resulting in the synthesis of a large number of genes, including bone marrow stromal antigen 2 (Bst2)/tetherin/CD317. Bst2 restricts the release of some enveloped viruses, but to date, its role in viral infection of neurons has not been assessed. Consequently, we investigated how Bst2 was induced and what role it played in MV neuronal infection. The magnitude of induction of neuronal Bst2 RNA and protein following IFN exposure and viral infection was notably higher than in similarly treated mouse embryo fibroblasts (MEFs). Bst2 synthesis was both IFN and Stat1 dependent. Although Bst2 prevented MV release from nonneuronal cells, its deletion had no effect on viral pathogenesis in MV-challenged mice. Our findings underscore how cell-type-specific differences impact viral infection and pathogenesis. IMPORTANCE Viral infections of the central nervous system can lead to debilitating disease and death. Moreover, it is becoming increasingly clear that nonrenewable cells, including most central nervous system neurons, combat neurotropic viral infections in fundamen-tally different ways than other rapidly dividing and renewable cell populations. Here we identify type I interferon signaling as a key inducer of a known antiviral protein (Bst2) in neurons. Unexpectedly, the gene is dispensable for clearance of neurotropic viral infection despite its well-defined contribution to limiting the spread of enveloped viruses in proliferating cells. A deeper appreciation of the importance of cell type heterogeneity in antiviral immunity will aid in the identification of unique therapeutic targets for life-threatening viral infections. Many of the foundational principles in immunology have resulted from basic observations of virus-cell interactions, including the induction and antiviral function of both type I and type II interferons (IFNs) (reviewed in references 1, 2, and 3). Viral infection of a cell typically results in cellular production and secretion of type I IFNs, which can then bind to cell surface receptors in a paracrine and autocrine fashion, leading to synthesis of interferon-stimulated genes (ISGs). These ISGs, in turn, aid in clearing the viral infection by directly cleaving viral nucleic acids, triggering cellular apoptosis, inducing autophagy, upregulating major histocompatibility complex (MHC) class I expression to aid in CD8 ϩ T cell-mediated cytotoxicity, and preventing viral egress. Moreover, the induction of type I IFN contributes to the recruitment of adaptive immune effectors to infected sites, which further promotes viral clearance.One ISG that is highly induced following infection by many viruses, and in response to both type I and II IFN signaling, is the gene for bone marrow stromal antigen 2 (Bst2; also known a...

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“…It has been shown that human tetherin (also termed BST2) interacts with Vpu (456)(457)(458)(459)(460)(461)(462)(463) and Nef (464). Meanwhile, CD4 physically binds to Vpu (14,19,433) and Nef (465).…”

Section: Vpu-tetherin/cd4-nef Associationmentioning

confidence: 99%

“…Different aspects of this mechanism have been reported. (i) HIV-1 Vpu hijacks trafficking pathways of the clathrin adaptor protein complex 1 (AP1) and adaptor protein complex 2 (AP2) to induce postendocytic membrane trafficking events that remove tetherin from the cell membrane (456,458). (ii) Despite the fact that tetherin enhances the susceptibility of HIV-infected cells to antibodies, HIV-1 Vpu and Nef antagonize tetherin to protect HIV-infected cells from antibody-dependent cell-mediated cytotoxicity, a type of human immune response where virus-specific antibodies activate the killing of HIV-infected cells (470)(471)(472).…”

Section: Vpu-tetherin/cd4-nef Associationmentioning

confidence: 99%

HIV Genome-Wide Protein Associations: a Review of 30 Years of Research

Clercq

2016

Microbiol Mol Biol Rev

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SUMMARYThe HIV genome encodes a small number of viral proteins (i.e., 16), invariably establishing cooperative associations among HIV proteins and between HIV and host proteins, to invade host cells and hijack their internal machineries. As a known example, the HIV envelope glycoprotein GP120 is closely associated with GP41 for viral entry. From a genome-wide perspective, a hypothesis can be worked out to determine whether 16 HIV proteins could develop 120 possible pairwise associations either by physical interactions or by functional associations mediated via HIV or host molecules. Here, we present the first systematic review of experimental evidence on HIV genome-wide protein associations using a large body of publications accumulated over the past 3 decades. Of 120 possible pairwise associations between 16 HIV proteins, at least 34 physical interactions and 17 functional associations have been identified. To achieve efficient viral replication and infection, HIV protein associations play essential roles (e.g., cleavage, inhibition, and activation) during the HIV life cycle. In either a dispensable or an indispensable manner, each HIV protein collaborates with another viral protein to accomplish specific activities that precisely take place at the proper stages of the HIV life cycle. In addition, HIV genome-wide protein associations have an impact on anti-HIV inhibitors due to the extensive cross talk between drug-inhibited proteins and other HIV proteins. Overall, this study presents for the first time a comprehensive overview of HIV genome-wide protein associations, highlighting meticulous collaborations between all viral proteins during the HIV life cycle.

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Structural basis of HIV-1 Vpu-mediated BST2 antagonism via hijacking of the clathrin adaptor protein complex 1

Cited by 90 publications

References 95 publications

Membrane Anchoring by a C-terminal Tryptophan Enables HIV-1 Vpu to Displace Bone Marrow Stromal Antigen 2 (BST2) from Sites of Viral Assembly

Membrane Anchoring by a C-terminal Tryptophan Enables HIV-1 Vpu to Displace Bone Marrow Stromal Antigen 2 (BST2) from Sites of Viral Assembly

Bst2/Tetherin Is Induced in Neurons by Type I Interferon and Viral Infection but Is Dispensable for Protection against Neurotropic Viral Challenge

HIV Genome-Wide Protein Associations: a Review of 30 Years of Research

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