βTrCP is Required for HIV-1 Vpu Modulation of CD4, GaLV Env, and BST-2/Tetherin

Song, Yul Eum; Cyburt, Daniel; Lucas, Tiffany M.; Gregory, Devon A.; Lyddon, Terri D.; Johnson, Marc C.

doi:10.3390/v10100573

Cited by 8 publications

(19 citation statements)

References 56 publications

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“…Phosphorylation of the serine residues of this motif allows the recruitment of the β-TrCP subunit of the SCF β-TrCP1/2 E3 ubiquitin ligase complex, leading to the ubiquitination and degradation of BST-2 in lysosomes (20, 21). Increasing evidence suggests that the recruitment of β-TrCP and the degradation of BST-2 by Vpu are dissociable from its ability to antagonize BST-2 (11, 14, 15, 18, 19, 22), although this is subject to debate (23).…”

Section: Introductionmentioning

confidence: 99%

Upregulation of BST-2 by Type I Interferons Reduces the Capacity of Vpu To Protect HIV-1-Infected Cells from NK Cell Responses

Prévost

Pickering

Mumby

et al. 2019

mBio

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The HIV-1 accessory protein Vpu enhances viral release by counteracting the restriction factor BST-2. Furthermore, Vpu promotes NK cell evasion by downmodulating cell surface NTB-A and PVR, known ligands of the NK cell receptors NTB-A and DNAM-1, respectively. While it has been established that Vpu’s transmembrane domain (TMD) is required for the interaction and intracellular sequestration of BST-2, NTB-A, and PVR, it remains unclear how Vpu manages to target these proteins simultaneously. In this study, we show that upon upregulation, BST-2 is preferentially downregulated by Vpu over its other TMD substrates. We found that type I interferon (IFN)-mediated BST-2 upregulation greatly impairs the ability of Vpu to downregulate NTB-A and PVR. Our results suggest that occupation of Vpu by BST-2 affects its ability to downregulate other TMD substrates. Accordingly, knockdown of BST-2 increases Vpu’s potency to downmodulate NTB-A and PVR in the presence of type I IFN treatment. Moreover, we show that expression of human BST-2, but not that of the macaque orthologue, decreases Vpu’s capacity to downregulate NTB-A. Importantly, we show that type I IFNs efficiently sensitize HIV-1-infected cells to NTB-A- and DNAM-1-mediated direct and antibody-dependent NK cell responses. Altogether, our results reveal that type I IFNs decrease Vpu’s polyfunctionality, thus reducing its capacity to protect HIV-1-infected cells from NK cell responses. IMPORTANCE The restriction factor BST-2 and the NK cell ligands NTB-A and PVR are among a growing list of membrane proteins found to be downregulated by HIV-1 Vpu. BST-2 antagonism enhances viral release, while NTB-A and PVR downmodulation contributes to NK cell evasion. However, it remains unclear how Vpu can target multiple cellular factors simultaneously. Here we provide evidence that under physiological conditions, BST-2 is preferentially targeted by Vpu over NTB-A and PVR. Specifically, we show that type I IFNs decrease Vpu’s polyfunctionality by upregulating BST-2, thus reducing its capacity to protect HIV-1-infected cells from NK cell responses. This indicates that there is a hierarchy of Vpu substrates upon IFN treatment, revealing that for the virus, targeting BST-2 as part of its resistance to IFN takes precedence over evading NK cell responses. This reveals a potential weakness in HIV-1’s immunoevasion mechanisms that may be exploited therapeutically to harness NK cell responses against HIV-1.

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Section: Introductionmentioning

confidence: 99%

Upregulation of BST-2 by Type I Interferons Reduces the Capacity of Vpu To Protect HIV-1-Infected Cells from NK Cell Responses

Prévost

Pickering

Mumby

et al. 2019

mBio

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“…In this study, we investigated the mechanism behind virus-specific incompatibility dependent on the Env CT. The GaLV Env CT incompatibility with HIV-1 has been extensively studied, and we along with others reported that the incompatibility was partly dependent on Vpu (8,20,25,26,44,45). Here, we addressed the GaLV Env CT incompatibility remaining in the absence of Vpu.…”

Section: Discussionmentioning

confidence: 97%

Sequence Determinants in Gammaretroviral Env Cytoplasmic Tails Dictate Virus-Specific Pseudotyping Compatibility

Song

Olinger

Janaka

et al. 2019

J Virol

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Viruses can incorporate foreign glycoproteins to form infectious particles through a process known as pseudotyping. However, not all glycoproteins are compatible with all viruses. Despite the fact that viral pseudotyping is widely used, what makes a virus/glycoprotein pair compatible is poorly understood. To study this, we chose to analyze a gammaretroviral glycoprotein (Env) whose compatibility with different viruses could be modulated through small changes in its cytoplasmic tail (CT). One form of this glycoprotein is compatible with murine leukemia virus (MLV) particles but incompatible with human immunodeficiency virus type 1 (HIV-1) particles, while the second is compatible with HIV-1 particles but not with MLV particles. To decipher the factors affecting virus-specific Env incompatibility, we characterized Env incorporation, maturation, cell-to-cell fusogenicity, and virus-to-cell fusogenicity of each Env. The HIV-1 particle incompatibility correlated with less efficient cleavage of the R peptide by HIV-1 protease. However, the MLV particle incompatibility was more nuanced. MLV incompatibility appeared to be caused by lack of incorporation into particles, yet incorporation could be restored by further truncating the CT or by using a chimeric MLV Gag protein containing the HIV-1 MA without fully restoring infectivity. The MLV particle incompatibility appeared to be caused in part by fusogenic repression in MLV particles through an unknown mechanism. This study demonstrates that the Env CT can dictate functionality of Env within particles in a virusspecific manner. IMPORTANCE Viruses utilize viral glycoproteins to efficiently enter target cells during infection. How viruses acquire viral glycoproteins has been studied to understand the pathogenesis of viruses and develop safer and more efficient viral vectors for gene therapies. The CTs of viral glycoproteins have been shown to regulate various stages of glycoprotein biogenesis, but a gap still remains in understanding the molecular mechanism of glycoprotein acquisition and functionality regarding the CT. Here, we studied the mechanism of how specific mutations in the CT of a gammaretroviral envelope glycoprotein distinctly affect infectivity of two different viruses. Different mutations caused failure of glycoproteins to function in a virus-specific manner due to distinct fusion defects, suggesting that there are virus-specific characteristics affecting glycoprotein functionality.

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“…HIV-1 accessory protein Vpu is well known to promote virus release from infected cells. Recent studies indicate that Vpu recruits tetherin, CD4, or P-selectin glycoprotein ligand 1 (PSGL-1) to CRL1 substrate receptor b-TRCP for ubiquitination and degradation [182,183]. Transmembrane protein tetherin functions as a tether between nascent virions and infected cells, as well as between nascent virions.…”

Section: Neddylation and Viral Infectionmentioning

confidence: 99%

“…It was shown to interact with tetherin through its transmembrane domain and with b-TRCP through its intracellular domain, followed by ubiquitination-induced endosomal degradation of tetherin [182,184]. Vpu targeted CD4 with its intracellular domain for ubiquitination and subsequent proteasomal degradation to avoid the re-adsorption of the nascent virions [182,183]. PSGL-1 is a transmembrane protein induced by IFN-c in activated CD4 + T cells.…”

Section: Neddylation and Viral Infectionmentioning

confidence: 99%

Diverse and pivotal roles of neddylation in metabolism and immunity

Zou

Zhang

2020

The FEBS Journal

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Neddylation is one type of protein post-translational modification by conjugating a ubiquitin-like protein neural precursor cell-expressed developmentally downregulated protein 8 to substrate proteins via a cascade involving E1, E2, and E3 enzymes. The best-characterized substrates of neddylation are cullins, essential components of cullin-RING E3 ubiquitinligase complexes. The discovery of noncullin neddylation targets indicates that neddylation may have diverse biological functions. Indeed, neddylation has been implicated in various cellular processes including cell cycle progression, metabolism, immunity, and tumorigenesis. Here, we summarized the reported neddylation substrates and also discuss the functions of neddylation in the immune system and metabolism.

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βTrCP is Required for HIV-1 Vpu Modulation of CD4, GaLV Env, and BST-2/Tetherin

Cited by 8 publications

References 56 publications

Upregulation of BST-2 by Type I Interferons Reduces the Capacity of Vpu To Protect HIV-1-Infected Cells from NK Cell Responses

Upregulation of BST-2 by Type I Interferons Reduces the Capacity of Vpu To Protect HIV-1-Infected Cells from NK Cell Responses

Sequence Determinants in Gammaretroviral Env Cytoplasmic Tails Dictate Virus-Specific Pseudotyping Compatibility

Diverse and pivotal roles of neddylation in metabolism and immunity

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