Tetherin/BST-2 Antagonism by Nef Depends on a Direct Physical Interaction between Nef and Tetherin, and on Clathrin-mediated Endocytosis

Serra-Moreno, Ruth; Zimmermann, Kerstin; Stern, Lawrence J.; Evans, David T.

doi:10.1371/journal.ppat.1003487

Cited by 55 publications

(93 citation statements)

References 63 publications

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“…In contrast, SIV Nef and HIV-2 Env do not mediate tetherin degradation but rather lead to tetherin's intracellular sequestration following enhanced internalization from the surface. This is dependent on AP2 binding sites in both viral proteins (18,(36)(37)(38)49). For Nef (36) and also for Env, as shown here, this does not require the presence of the endocytic signal in tetherin itself.…”

Section: Discussionsupporting

confidence: 50%

“…Most SIVs that lack a vpu gene antagonize their species' tetherins with Nef (15,16). SIVmac Nef binds to the cytoplasmic tail of macaque tetherin and likely forms a ternary complex with clathrin adaptor protein complex 2 (AP2) (36,37) to stimulate tetherin endocytosis and intracellular sequestration. Nef's specificity for primate tetherins depends on a (G/D)DIWK motif that is absent from human tetherin.…”

Section: Resultsmentioning

confidence: 99%

“…However, a serine-threonine motif found only in L-tetherin has been highlighted as important (35). In contrast, other lentiviral tetherin antagonists do not mediate its degradation but rather promote its endocytosis from the PM for intracellular sequestration (15,18,(36)(37)(38).…”

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confidence: 99%

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Differential Sensitivities of Tetherin Isoforms to Counteraction by Primate Lentiviruses

Weinelt

Neil

2014

J Virol

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The mammalian antiviral membrane protein tetherin (BST2/CD317) can be expressed as two isoforms derived from differential translational initiation. The shorter isoform of the human protein (S-tetherin) lacks the first 12 amino acids of the longer (Ltetherin) cytoplasmic tail, which includes a tyrosine motif that acts as both an endocytic recycling signal and a determinant of virus-induced NF-B activation. S-tetherin is also reported to be less sensitive to the prototypic viral antagonist human immunodeficiency virus type 1 (HIV-1) Vpu. Here we analyzed the relative sensitivities of L-and S-tetherins to primate lentiviral countermeasures. We show that the reduced sensitivity of S-tetherin to HIV-1 Vpu is a feature of all group M proteins, including those of transmitted founder viruses, primarily because it cannot be targeted for endosomal degradation owing to the truncation of its cytoplasmic tail. In contrast, both isoforms of the human and rhesus macaque tetherins display the same sensitivity to nondegradative lentiviral countermeasures of HIV-2 and SIVmac, respectively. Surprisingly, however, the Vpu proteins encoded by simian immunodeficiency viruses (SIVs) of African guenons, as well as that from recently isolated highly pathogenic HIV-1 group N, do not discriminate between tetherin isoforms. Together, these data suggest that the group M HIV-1 Vpu primarily adapted to target L-tetherin upon zoonotic transmission from chimpanzees, and further, we speculate that functions specifically associated with this isoform, such as proinflammatory signaling, play key roles in human tetherin's antiviral function in vivo. IMPORTANCEThe ability of HIV-1 and related viruses to counteract a host antiviral protein, tetherin, is strictly maintained. The adaptation of the HIV-1 Vpu protein to counteract human tetherin is thought to have been one of the key events in the establishment of the HIV/AIDS pandemic. Recent evidence shows that tetherin is expressed as two isoforms and that Vpu preferentially targets the longer form. Here we show that unlike other virus-encoded countermeasures, such as those from primate viruses related to HIV-1, the enhanced ability to counteract the long tetherin isoform is conserved among HIV-1 strains that make up the majority of the human pandemic. This correlates with the ability of Vpu to induce long tetherin degradation. We speculate that functions associated with the human version of this isoform, such as an inflammatory signaling capacity, selected for Vpu's enhanced targeting of long tetherin during its adaptation to humans.

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Section: Discussionsupporting

confidence: 50%

Section: Resultsmentioning

confidence: 99%

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Differential Sensitivities of Tetherin Isoforms to Counteraction by Primate Lentiviruses

Weinelt

Neil

2014

J Virol

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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 to immune cells and rapidly dividing cell types such as fibroblasts (21).…”

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%

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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Tetherin/BST-2 Antagonism by Nef Depends on a Direct Physical Interaction between Nef and Tetherin, and on Clathrin-mediated Endocytosis

Cited by 55 publications

References 63 publications

Differential Sensitivities of Tetherin Isoforms to Counteraction by Primate Lentiviruses

Differential Sensitivities of Tetherin Isoforms to Counteraction by Primate Lentiviruses

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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