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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA-Binding Proteins / metabolism
  • Endodeoxyribonucleases / metabolism
  • Endonucleases / metabolism
  • G2 Phase Cell Cycle Checkpoints*
  • HEK293 Cells
  • HIV Infections / immunology
  • HIV Infections / pathology*
  • HIV Infections / virology
  • HIV-1 / metabolism*
  • HeLa Cells
  • Humans
  • Immunity, Innate*
  • Interferon-gamma / metabolism
  • Multiprotein Complexes / metabolism*
  • Recombinases / metabolism*
  • vpr Gene Products, Human Immunodeficiency Virus / metabolism*

Substances

  • DNA-Binding Proteins
  • Multiprotein Complexes
  • Recombinases
  • vpr Gene Products, Human Immunodeficiency Virus
  • Interferon-gamma
  • Eme1 protein, human
  • Endodeoxyribonucleases
  • Endonucleases
  • MUS81 protein, human
  • SLX4 protein, human