Premature Activation of the SLX4 Complex by Vpr Promotes G2/M Arrest and Escape from Innate Immune Sensing

Laguette, Nadine; Brégnard, Christelle; Hue, Pauline; Basbous, Jihane; Yatim, Ahmad; Larroque, Marion; Kirchhoff, Frank; Constantinou, Angelos; Sobhian, Bijan; Benkirane, Monsef

doi:10.1016/j.cell.2013.12.011

Cited by 194 publications

(309 citation statements)

References 62 publications

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“…Furthermore, the partial ability of the G2 arrest-defective Vpr S79A mutant to induce HLTF degradation suggests that a block in the cell cycle is not a prerequisite for the modulation of HLTF expression. Vpr triggers the degradation of the SLX4-associated Mus81 endonuclease, although conflicting results have been reported regarding the link between Vpr-mediated Mus81 degradation and G2 arrest (30,61). We confirmed that Vpr degrades both Mus81 and HLTF and that this degradation required DCAF1 (Fig.…”

Section: Resultssupporting

confidence: 75%

“…This hypothesis was attractive because both Vpr and depletion of some DNA translocases having apparent redundant function with HLTF interfere with SLX4com. For example, SWI/SNFrelated matrix-associated actin-dependent regulator of chromatin subfamily A-like protein 1 (SMARCAL1) was reported to interfere with MUS81 structure-specific endonuclease subunit (Mus81) or the SLX4 endonuclease complex and the repair of damaged replication forks (30,70,71). However, several lines of evidence suggest that HLTF is not involved in the cytostatic activity of Vpr.…”

Section: Resultsmentioning

confidence: 98%

“…SLX4com associates with several endonucleases, including Mus81, to coordinate the repair of specific replication-born double strand breaks (DSBs) and collapsed replication forks (31)(32)(33). It has been proposed that Vpr triggers replication stress and G2 arrest through inappropriate activation of SLX4com (30). This activation would lead to the elimination of viral DNA and, subsequently, virus escape from immune sensing.…”

mentioning

confidence: 99%

“…G2 arrest requires Vpr binding to DCAF1, an adaptor of the Cul4A-DDB1 ubiquitin ligase, which is involved in DNA repair in noninfected cells (23)(24)(25)(26)(27)(28)(29). More recently, Vpr has been shown to activate the SLX4 complex (SLX4com) with the help of DCAF1 (21,30). SLX4com associates with several endonucleases, including Mus81, to coordinate the repair of specific replication-born double strand breaks (DSBs) and collapsed replication forks (31)(32)(33).…”

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confidence: 99%

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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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Section: Resultssupporting

confidence: 75%

Section: Resultsmentioning

confidence: 98%

mentioning

confidence: 99%

mentioning

confidence: 99%

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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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“…In particular, Vpr was shown to directly bind SLX4 and was postulated to untimely activate the SLX4com via the CRL4-DCAF1 complex. These interactions were proposed to lead to aberrant DNA cleavage and cell cycle arrest (54). Additionally, MUS81 was reported to be down-regulated by Vpr, which was further confirmed by another two groups (55,56).…”

supporting

confidence: 50%

SLX4-SLX1 Protein-independent Down-regulation of MUS81-EME1 Protein by HIV-1 Viral Protein R (Vpr)

Zhou

DeLucia

Ahn

2016

Journal of Biological Chemistry

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Evolutionarily conserved structure-selective endonuclease MUS81 forms a complex with EME1 and further associates with another endonuclease SLX4-SLX1 to form a four-subunit complex of MUS81-EME1-SLX4-SLX1, coordinating distinctive biochemical activities of both endonucleases in DNA repair. Viral protein R (Vpr), a highly conserved accessory protein in primate lentiviruses, was previously reported to bind SLX4 to mediate down-regulation of MUS81. However, the detailed mechanism underlying MUS81 down-regulation is unclear. Here, we report that HIV-1 Vpr down-regulates both MUS81 and its cofactor EME1 by hijacking the host CRL4-DCAF1 E3 ubiquitin ligase. Multiple Vpr variants, from HIV-1 and SIV, down-regulate both MUS81 and EME1. Furthermore, a C-terminally truncated Vpr mutant and point mutants R80A and Q65R, all of which lack G 2 arrest activity, are able to downregulate MUS81-EME1, suggesting that Vpr-induced G 2 arrest is not correlated with MUS81-EME1 down-regulation. We also show that neither the interaction of MUS81-EME1 with Vpr nor their down-regulation is dependent on SLX4-SLX1. Together, these data provide new insight on a conserved function of Vpr in a host endonuclease down-regulation.

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Interferons and beyond: Induction of antiretroviral restriction factors

Hotter

Kirchhoff

2017

Journal of Leukocyte Biology

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Antiviral restriction factors are structurally and functionally diverse cellular proteins that play a key role in the first line of defense against viral pathogens. Although many cell types constitutively express restriction factors at low levels, their induction in response to viral exposure and replication is often required for potent control and repulse of the invading pathogens. It is well established that type I IFNs efficiently induce antiviral restriction factors. Accumulating evidence suggests that other types of IFN, as well as specific cytokines, such as IL-27, and other activators of the cell are also capable of enhancing the expression of restriction factors and hence to establish an antiviral cellular state. Agents that efficiently induce restriction factors, increase their activity, and/or render them resistant against viral antagonists without causing general inflammation and significant side effects hold some promise for novel therapeutic or preventive strategies. In the present review, we summarize some of the current knowledge on the induction of antiretroviral restriction factors and perspectives for therapeutic application.

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Premature Activation of the SLX4 Complex by Vpr Promotes G2/M Arrest and Escape from Innate Immune Sensing

Cited by 194 publications

References 62 publications

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

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

SLX4-SLX1 Protein-independent Down-regulation of MUS81-EME1 Protein by HIV-1 Viral Protein R (Vpr)

Interferons and beyond: Induction of antiretroviral restriction factors

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