Premature activation of the SLX4 complex by Vpr promotes G2/M arrest and escape from innate immune sensing.
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.
Mesh Terms:
DNA-Binding Proteins, Endodeoxyribonucleases, Endonucleases, G2 Phase Cell Cycle Checkpoints, HEK293 Cells, HIV Infections, HIV-1, HeLa Cells, Humans, Immunity, Innate, Interferon-gamma, Multiprotein Complexes, Recombinases, vpr Gene Products, Human Immunodeficiency Virus
DNA-Binding Proteins, Endodeoxyribonucleases, Endonucleases, G2 Phase Cell Cycle Checkpoints, HEK293 Cells, HIV Infections, HIV-1, HeLa Cells, Humans, Immunity, Innate, Interferon-gamma, Multiprotein Complexes, Recombinases, vpr Gene Products, Human Immunodeficiency Virus
Cell
Date: Jan. 16, 2014
PubMed ID: 24412650
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