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

Abstract : The HIV auxiliary protein Vpr potently blocks the cell cycle at the G2/M transition. Here, we show that G2/M arrest results from untimely activation of the structure-specific endonuclease (SSE) regulator SLX4 complex (SLX4com) by Vpr, a process that requires VPRBP-DDB1-CUL4 E3-ligase complex. Direct interaction of Vpr with SLX4 induced the recruitment of VPRBP and kinase-active PLK1, enhancing the cleavage of DNA by SLX4-associated MUS81-EME1 endonucleases. G2/M arrest-deficient Vpr alleles failed to interact with SLX4 or to induce recruitment of MUS81 and PLK1. Furthermore, knockdown of SLX4, MUS81, or EME1 inhibited Vpr-induced G2/M arrest. In addition, we show that the SLX4com is involved in suppressing spontaneous and HIV-1-mediated induction of type 1 interferon and establishment of antiviral responses. Thus, our work not only reveals the identity of the cellular factors required for Vpr-mediated G2/M arrest but also identifies the SLX4com as a regulator of innate immunity.
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https://hal.archives-ouvertes.fr/hal-00957510
Contributor : Catherine Larose <>
Submitted on : Monday, March 10, 2014 - 3:27:53 PM
Last modification on : Thursday, November 5, 2020 - 9:26:04 AM

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Nadine Laguette, Christelle Brégnard, Pauline Hue, Jihane Basbous, Ahmad Yatim, et al.. Premature Activation of the SLX4 Complex by Vpr Promotes G2/M Arrest and Escape from Innate Immune Sensing. Cell, Elsevier, 2014, 156 (1-2), pp.134-145. ⟨10.1016/j.cell.2013.12.011⟩. ⟨hal-00957510⟩

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