HIV-1 Vpr Protein Induces Proteasomal Degradation of Chromatin-associated Class I HDACs to Overcome Latent Infection of Macrophages

Romani, Bizhan; Baygloo, Nima Shaykh; Hamidi-Fard, Mojtaba; Aghasadeghi, Mohammad Reza; Allahbakhshi, Elham

doi:10.1074/jbc.m115.689018

Cited by 36 publications

(38 citation statements)

References 39 publications

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“…HDAC2 and HDAC8 were not noticeably affected by Vpr in any of the fractions. Of note, this was expected since our previous study also showed that depletion of HDAC2 and 8 only occurs at high expression levels of Vpr, at an MOI of 2.0 or higher28. Here we also showed that Vpr was able to induce depletion of all the four members of class I HDACs, including HDAC1, HDAC2, HDAC3, and HDAC8 in J-Lat cells when transduced at an MOI of 5.0 (Supplementary Fig.…”

Section: Resultssupporting

confidence: 83%

“…We have recently reported that HIV-1 Vpr induces proteasomal degradation of class I HDACs in a localized manner which is more focused on the chromatin. This effect of Vpr was found to counteract silent infection of macrophages by maintaining an active LTR during infection28. In this study, we examined whether Vpr has an effect on class I HDACs and reactivation of the HIV-1 provirus in latently infected cells.…”

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confidence: 99%

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HIV-1 Vpr reactivates latent HIV-1 provirus by inducing depletion of class I HDACs on chromatin

Romani

Jamil

Hamidi-Fard

et al. 2016

Sci Rep

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HIV-1 Vpr is an accessory protein that induces proteasomal degradation of multiple proteins. We recently showed that Vpr targets class I HDACs on chromatin for proteasomal degradation. Here we show that Vpr induces degradation of HDAC1 and HDAC3 in HIV-1 latently infected J-Lat cells. Degradation of HDAC1 and HDAC3 was also observed on the HIV-1 LTR and as a result, markers of active transcription were recruited to the viral promoter and induced viral activation. Knockdown of HDAC1 and HDAC3 activated the latent HIV-1 provirus and complementation with HDAC3 inhibited Vpr-induced HIV-1 reactivation. Viral reactivation and degradation of HDAC1 and HDAC3 was conserved among Vpr proteins of HV-1 group M. Serum Vpr isolated from patients or the release of virion-incorporated Vpr from viral lysates also activated HIV-1 in latently infected cell lines and PBMCs from HIV-1 infected patients. Our results indicate that Vpr counteracts HIV-1 latency by inducing proteasomal degradation of HDAC1 and 3 leading to reactivation of the viral promoter.

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Section: Resultssupporting

confidence: 83%

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confidence: 99%

HIV-1 Vpr reactivates latent HIV-1 provirus by inducing depletion of class I HDACs on chromatin

Romani

Jamil

Hamidi-Fard

et al. 2016

Sci Rep

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“…Surprisingly, HLTF was the sole cellular target that was clearly down-regulated in the presence of HIV-1 Vpr, among more than 2,000 proteins quantified. Several other host proteins have been proposed to be targeted by Vpr, but previous results were mostly based on candidate-based approaches and with often modest down-regulation (62)(63)(64). Importantly, HLTF is down-regulated by Vpr in infected T cells.…”

Section: Resultsmentioning

confidence: 99%

HIV-1 Vpr degrades the HLTF DNA translocase in T cells and macrophages

Lahouassa

Blondot

Chauveau

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Viruses often interfere with the DNA damage response to better replicate in their hosts. The human immunodeficiency virus 1 (HIV-1) viral protein R (Vpr) protein has been reported to modulate the activity of the DNA repair structure-specific endonuclease subunit (SLX4) complex and to promote cell cycle arrest. Vpr also interferes with the base-excision repair pathway by antagonizing the uracil DNA glycosylase (Ung2) enzyme. Using an unbiased quantitative proteomic screen, we report that Vpr down-regulates helicase-like transcription factor (HLTF), a DNA translocase involved in the repair of damaged replication forks. Vpr subverts the DDB1-cullin4-associatedfactor 1 (DCAF1) adaptor of the Cul4A ubiquitin ligase to trigger proteasomal degradation of HLTF. This event takes place rapidly after Vpr delivery to cells, before and independently of Vpr-mediated G2 arrest. HLTF is degraded in lymphocytic cells and macrophages infected with Vpr-expressing HIV-1. Our results reveal a previously unidentified strategy for HIV-1 to antagonize DNA repair in host cells.HIV | restriction factor | DNA repair | Vpr target | SILAC

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“…Particularly, the ubiquitin dependent degradation pathway is one of the attractive machineries manipulated by multiple accessory proteins, such as, Vif, Vpu, and Vpx, of primate lentiviruses. Predominantly, Vpr was found to invoke increasingly numerous host factors for proteasome dependent degradation, such as MCM10, MUS81, helicase-like transcription factor (HLTF), Exonuclease 1 (Exo1), and histone deacetylases (HDACs) [35][36][37]47,48]. Interestingly, these cellular targets also respond to DNA damage from viruses or other environmental stimulants.…”

Section: Discussionmentioning

confidence: 99%

Distinct MCM10 Proteasomal Degradation Profiles by Primate Lentiviruses Vpr Proteins

Chang

Siarot

Matsuura

et al. 2020

Viruses

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Viral protein R (Vpr) is an accessory protein found in various primate lentiviruses, including human immunodeficiency viruses type 1 and 2 (HIV-1 and HIV-2) as well as simian immunodeficiency viruses (SIVs). Vpr modulates many processes during viral lifecycle via interaction with several of cellular targets. Previous studies showed that HIV-1 Vpr strengthened degradation of Mini-chromosome Maintenance Protein10 (MCM10) by manipulating DCAF1-Cul4-E3 ligase in proteasome-dependent pathway. However, whether Vpr from other primate lentiviruses are also associated with MCM10 degradation and the ensuing impact remain unknown. Based on phylogenetic analyses, a panel of primate lentiviruses Vpr/x covering main virus lineages was prepared. Distinct MCM10 degradation profiles were mapped and HIV-1, SIVmus and SIVrcm Vprs induced MCM10 degradation in proteasome-dependent pathway. Colocalization and interaction between MCM10 with these Vprs were also observed. Moreover, MCM10 2-7 interaction region was identified as a determinant region susceptible to degradation. However, MCM10 degradation did not alleviate DNA damage response induced by these Vpr proteins. MCM10 degradation by HIV-1 Vpr proteins was correlated with G2/M arrest, while induction of apoptosis and oligomerization formation of Vpr failed to alter MCM10 proteolysis. The current study demonstrated a distinct interplay pattern between primate lentiviruses Vpr proteins and MCM10.

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HIV-1 Vpr Protein Induces Proteasomal Degradation of Chromatin-associated Class I HDACs to Overcome Latent Infection of Macrophages

Cited by 36 publications

References 39 publications

HIV-1 Vpr reactivates latent HIV-1 provirus by inducing depletion of class I HDACs on chromatin

HIV-1 Vpr reactivates latent HIV-1 provirus by inducing depletion of class I HDACs on chromatin

HIV-1 Vpr degrades the HLTF DNA translocase in T cells and macrophages

Distinct MCM10 Proteasomal Degradation Profiles by Primate Lentiviruses Vpr Proteins

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