HIV-1 Vpr counteracts HLTF-mediated restriction of HIV-1 infection in T cells

Yan, Junpeng; Shun, Ming-Chieh; Zhang, Yi; Hao, Caili; Skowroński, Jacek

doi:10.1073/pnas.1818401116

Cited by 36 publications

(40 citation statements)

References 83 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previous studies suggested that HIV-1 Vpr antagonizes several post-replication DNA repair machineries by usurping the CRL4-DCAF1. Importantly, recent reports showed that removal of HLTF and EXO1 is beneficial to HIV-1 replication (26,33). The observation that removal of these proteins only partially accounts for the phenotypic effect of Vpr implicates the existence of additional Vpr-counteracted machineries that restrict viral replication.…”

Section: Several Studies Have Suggested a Functional Link Between Hismentioning

confidence: 99%

HIV-1 Vpr activates host CRL4-DCAF1 E3 ligase to degrade histone deacetylase SIRT7

Zhou

Monnie

DeLucia

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: Vpr is a virion-associated protein that is encoded by lentiviruses and serves to counteract intrinsic immunity factors that restrict infection. HIV-1 Vpr mediates proteasome-dependent degradation of several DNA repair/modification proteins. Mechanistically, Vpr directly recruits cellular targets onto DCAF1, a substrate receptor of Cullin 4 RING E3 ubiquitin ligase (CRL4) for poly-ubiquitination. Further, Vpr can mediate poly-ubiquitination of DCAF1-interacting proteins by the CRL4. Because Vpr-mediated degradation of its known targets can not explain the primary cell-cycle arrest phenotype that Vpr expression induces, we surveyed the literature for DNA-repair-associated proteins that interact with the CRL4-DCAF1. One such protein is SIRT7, a deacetylase of histone 3 that belongs to the Sirtuin family and regulates a wide range of cellular processes. We wondered whether Vpr can mediate degradation of SIRT7 via the CRL4-DCAF1. Methods: HEK293T cells were transfected with cocktails of plasmids expressing DCAF1, DDB1, SIRT7 and Vpr. Ectopic and endogeneous levels of SIRT7 were monitered by immunoblotting and protein-protein interactions were assessed by immunoprecipitation. For in vitro reconstitution assays, recombinant CRL4-DCAF1-Vpr complexes and SIRT7 were prepared and poly-ubiqutination of SIRT7 was monitored with immunoblotting. Results: We demonstrate SIRT7 polyubiquitination and degradation upon Vpr expression. Specifically, SIRT7 is shown to interact with the CRL4-DCAF1 complex, and expression of Vpr in HEK293T cells results in SIRT7 degradation, which is partially rescued by CRL inhibitor MNL4924 and proteasome inhibitor MG132. Further, in vitro reconstitution assays show that Vpr induces poly-ubiquitination of SIRT7 by the CRL4-DCAF1. Importantly, we find that Vpr from several different HIV-1 strains, but not HIV-2 strains, mediates SIRT7 poly-ubiquitination in the reconstitution assay and degradation in cells. Finally, we show that SIRT7 degradation by Vpr is independent of the known, distinctive phenotype of Vpr-induced cell cycle arrest at the G2 phase, Conclusions: Targeting histone deacetylase SIRT7 for degradation is a conserved feature of HIV-1 Vpr. Altogether , our findings reveal that HIV-1 Vpr mediates down-regulation of SIRT7 by a mechanism that does not involve novel target recruitment to the CRL4-DCAF1 but instead involves regulation of the E3 ligase activity.

show abstract

Section: Several Studies Have Suggested a Functional Link Between Hismentioning

confidence: 99%

HIV-1 Vpr activates host CRL4-DCAF1 E3 ligase to degrade histone deacetylase SIRT7

Zhou

Monnie

DeLucia

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Recently, it was found that HIV-1 Vpu targets additional ISGs including CD99, PLP2, and UBE2L6 for proteolytic degradation in a manner mechanistically similar to antagonism of BST2 [99][100][101][102]. HIV-1 Vpr and its Vpr/Vpx homologs in HIV-2 and SIV associate with the cullin4A-DDB1-DCAF1 complex to target multiple host factors including tet methylcytosine dioxygenase 2 (TET2) and helicase-like transcription factor (HLTF) for degradation, thus promoting virus infection [103,104]. This interaction is also essential for Vpx-induced degradation of SAMHD1, facilitating reverse transcription in myeloid and resting T cells, as mentioned above [18,19,105].…”

Section: Counteraction Of Hiv-1 Restriction Factorsmentioning

confidence: 99%

Sensor Sensibility—HIV-1 and the Innate Immune Response

Yin

Langer

Zhang

et al. 2020

Cells

View full text Add to dashboard Cite

Innate immunity represents the human immune system’s first line of defense against a pathogenic intruder and is initiated by the recognition of conserved molecular structures known as pathogen-associated molecular patterns (PAMPs) by specialized cellular sensors, called pattern recognition receptors (PRRs). Human immunodeficiency virus type 1 (HIV-1) is a unique human RNA virus that causes acquired immunodeficiency syndrome (AIDS) in infected individuals. During the replication cycle, HIV-1 undergoes reverse transcription of its RNA genome and integrates the resulting DNA into the human genome. Subsequently, transcription of the integrated provirus results in production of new virions and spreading infection of the virus. Throughout the viral replication cycle, numerous nucleic acid derived PAMPs can be recognized by a diverse set of innate immune sensors in infected cells. However, HIV-1 has evolved efficient strategies to evade or counteract this immune surveillance and the downstream responses. Understanding the molecular underpinnings of the concerted actions of the innate immune system, as well as the corresponding viral evasion mechanisms during infection, is critical to understanding HIV-1 transmission and pathogenesis, and may provide important guidance for the design of appropriate adjuvant and vaccine strategies. Here, we summarize current knowledge of the molecular basis for sensing HIV-1 in human cells, including CD4+ T cells, dendritic cells, and macrophages. Furthermore, we discuss the underlying mechanisms by which innate sensing is regulated, and describe the strategies developed by HIV-1 to evade sensing and immune responses.

show abstract

“…Vpr causes ubiquitination and subsequent proteasomal degradation of helicase-like transcription factor (HLTF), a multi-domain, multi-functional protein that activates post-replication DNA repair [156,157]. Vpr-mediated degradation of HLTF enhances HIV replication in CD4 + T cells, but this effect is only apparent in competition assays [158]. Moreover, silencing HLTF did not fully restore replication by the Vpr mutant, indicating that Vpr has additional functions.…”

Section: Vpr's Role In Viral Replicationmentioning

confidence: 99%

Vpr Is a VIP: HIV Vpr and Infected Macrophages Promote Viral Pathogenesis

Lubow

Collins

2020

Viruses

View full text Add to dashboard Cite

HIV infects several cell types in the body, including CD4+ T cells and macrophages. Here we review the role of macrophages in HIV infection and describe complex interactions between viral proteins and host defenses in these cells. Macrophages exist in many forms throughout the body, where they play numerous roles in healthy and diseased states. They express pattern-recognition receptors (PRRs) that bind viral, bacterial, fungal, and parasitic pathogens, making them both a key player in innate immunity and a potential target of infection by pathogens, including HIV. Among these PRRs is mannose receptor, a macrophage-specific protein that binds oligosaccharides, restricts HIV replication, and is downregulated by the HIV accessory protein Vpr. Vpr significantly enhances infection in vivo, but the mechanism by which this occurs is controversial. It is well established that Vpr alters the expression of numerous host proteins by using its co-factor DCAF1, a component of the DCAF1–DDB1–CUL4 ubiquitin ligase complex. The host proteins targeted by Vpr and their role in viral replication are described in detail. We also discuss the structure and function of the viral protein Env, which is stabilized by Vpr in macrophages. Overall, this literature review provides an updated understanding of the contributions of macrophages and Vpr to HIV pathogenesis.

show abstract

HIV-1 Vpr counteracts HLTF-mediated restriction of HIV-1 infection in T cells

Cited by 36 publications

References 83 publications

HIV-1 Vpr activates host CRL4-DCAF1 E3 ligase to degrade histone deacetylase SIRT7

HIV-1 Vpr activates host CRL4-DCAF1 E3 ligase to degrade histone deacetylase SIRT7

Sensor Sensibility—HIV-1 and the Innate Immune Response

Vpr Is a VIP: HIV Vpr and Infected Macrophages Promote Viral Pathogenesis

Contact Info

Product

Resources

About