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

Nadine Laguette (1) , Christelle Brégnard (1) , Pauline Hue (1) , J. Basbous (1) , Ahmad Yatim (1) , Marion Larroque (1) , Frank Kirchhoff (2) , Angelos Constantinou (1) , Bijan Sobhian (1) , Monsef Benkirane (1)

1 IGH - Institut de génétique humaine
2 Institute of Molecular Virology

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.

Domaines: Génétique

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