title: 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.
authors.affiliation: Institut de Génétique Humaine, Laboratoire de Virologie Moléculaire, CNRS UPR1142, Montpellier 34000, France. Electronic address: nadine.laguette@igh.cnrs.fr.
authors.forename: Nadine
authors.initials: N
authors.lastname: Laguette
authors.affiliation: Institut de Génétique Humaine, Laboratoire de Virologie Moléculaire, CNRS UPR1142, Montpellier 34000, France.
authors.forename: Christelle
authors.initials: C
authors.lastname: Brégnard
authors.affiliation: Institut de Génétique Humaine, Laboratoire de Virologie Moléculaire, CNRS UPR1142, Montpellier 34000, France.
authors.forename: Pauline
authors.initials: P
authors.lastname: Hue
authors.affiliation: Laboratoire Instabilité du Génome et Cancer, CNRS UPR1142, Montpellier 34000, France.
authors.forename: Jihane
authors.initials: J
authors.lastname: Basbous
authors.affiliation: Institut de Génétique Humaine, Laboratoire de Virologie Moléculaire, CNRS UPR1142, Montpellier 34000, France.
authors.forename: Ahmad
authors.initials: A
authors.lastname: Yatim
authors.affiliation: Laboratoire Instabilité du Génome et Cancer, CNRS UPR1142, Montpellier 34000, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Larroque
authors.affiliation: Institute of Molecular Virology, Ulm University Medical Center, 81089 Ulm, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Kirchhoff
authors.affiliation: Laboratoire Instabilité du Génome et Cancer, CNRS UPR1142, Montpellier 34000, France.
authors.forename: Angelos
authors.initials: A
authors.lastname: Constantinou
authors.affiliation: Institut de Génétique Humaine, Laboratoire de Virologie Moléculaire, CNRS UPR1142, Montpellier 34000, France.
authors.forename: Bijan
authors.initials: B
authors.lastname: Sobhian
authors.affiliation: Institut de Génétique Humaine, Laboratoire de Virologie Moléculaire, CNRS UPR1142, Montpellier 34000, France. Electronic address: monsef.benkirane@igh.cnrs.fr.
authors.forename: Monsef
authors.initials: M
authors.lastname: Benkirane
mesh_terms: D004268:DNA-Binding Proteins / Q000378:metabolism; D004706:Endodeoxyribonucleases / Q000378:metabolism; D004720:Endonucleases / Q000378:metabolism; D059565:G2 Phase Cell Cycle Checkpoints; D057809:HEK293 Cells; D015658:HIV Infections / Q000276:immunology / Q000473:pathology* / Q000821:virology; D015497:HIV-1 / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D007113:Immunity, Innate; D007371:Interferon-gamma / Q000378:metabolism; D046912:Multiprotein Complexes / Q000378:metabolism*; D045522:Recombinases / Q000378:metabolism*; D054325:vpr Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D046912:Multiprotein Complexes; D045522:Recombinases; D054325:vpr Gene Products, Human Immunodeficiency Virus; D007371:Interferon-gamma; C507947:Eme1 protein, human; D004706:Endodeoxyribonucleases; D004720:Endonucleases; C498772:MUS81 protein, human; C542319:SLX4 protein, human