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Cell. 2014 Jan 16;156(1-2):134-45. doi: 10.1016/j.cell.2013.12.011. Epub 2014 Jan 9.

Premature activation of the SLX4 complex by Vpr promotes G2/M arrest and escape from innate immune sensing.

Author information

1
Institut de Génétique Humaine, Laboratoire de Virologie Moléculaire, CNRS UPR1142, Montpellier 34000, France. Electronic address: nadine.laguette@igh.cnrs.fr.
2
Institut de Génétique Humaine, Laboratoire de Virologie Moléculaire, CNRS UPR1142, Montpellier 34000, France.
3
Laboratoire Instabilité du Génome et Cancer, CNRS UPR1142, Montpellier 34000, France.
4
Institute of Molecular Virology, Ulm University Medical Center, 81089 Ulm, Germany.
5
Institut de Génétique Humaine, Laboratoire de Virologie Moléculaire, CNRS UPR1142, Montpellier 34000, France. Electronic address: monsef.benkirane@igh.cnrs.fr.

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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PMID:
24412650
DOI:
10.1016/j.cell.2013.12.011
[Indexed for MEDLINE]
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