title: HIV-1 Vpr induces the degradation of ZIP and sZIP, adaptors of the NuRD chromatin remodeling complex, by hijacking DCAF1/VprBP.
abstract: The Vpr protein from type 1 and type 2 Human Immunodeficiency Viruses (HIV-1 and HIV-2) is thought to inactivate several host proteins through the hijacking of the DCAF1 adaptor of the Cul4A ubiquitin ligase. Here, we identified two transcriptional regulators, ZIP and sZIP, as Vpr-binding proteins degraded in the presence of Vpr. ZIP and sZIP have been shown to act through the recruitment of the NuRD chromatin remodeling complex. Strikingly, chromatin is the only cellular fraction where Vpr is present together with Cul4A ubiquitin ligase subunits. Components of the NuRD complex and exogenous ZIP and sZIP were also associated with this fraction. Several lines of evidence indicate that Vpr induces ZIP and sZIP degradation by hijacking DCAF1: (i) Vpr induced a drastic decrease of exogenously expressed ZIP and sZIP in a dose-dependent manner, (ii) this decrease relied on the proteasome activity, (iii) ZIP or sZIP degradation was impaired in the presence of a DCAF1-binding deficient Vpr mutant or when DCAF1 expression was silenced. Vpr-mediated ZIP and sZIP degradation did not correlate with the growth-related Vpr activities, namely G2 arrest and G2 arrest-independent cytotoxicity. Nonetheless, infection with HIV-1 viruses expressing Vpr led to the degradation of the two proteins. Altogether our results highlight the existence of two host transcription factors inactivated by Vpr. The role of Vpr-mediated ZIP and sZIP degradation in the HIV-1 replication cycle remains to be deciphered.
authors.affiliation: Institut National de la Sante et de la recherche Medicale Inserm U1016, Institut Cochin, Paris, France ; CNRS UMR8104, Paris, France ; University Paris Descartes, Paris, France ; Institute for Molecular Infection Biology, University of Würzburg, Würzburg, Germany.
authors.forename: Claire
authors.initials: C
authors.lastname: Maudet
authors.forename: Adèle
authors.initials: A
authors.lastname: Sourisce
authors.forename: Loïc
authors.initials: L
authors.lastname: Dragin
authors.forename: Hichem
authors.initials: H
authors.lastname: Lahouassa
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Rain
authors.forename: Serge
authors.initials: S
authors.lastname: Bouaziz
authors.forename: Bertha Cécilia
authors.initials: BC
authors.lastname: Ramirez
authors.forename: Florence
authors.initials: F
authors.lastname: Margottin-Goguet
mesh_terms: D002352:Carrier Proteins / Q000378:metabolism*; D042002:Chromatin Assembly and Disassembly; D057809:HEK293 Cells; D015658:HIV Infections / Q000378:metabolism*; D015497:HIV-1 / Q000502:physiology*; D006367:HeLa Cells; D054884:Host-Pathogen Interactions; D006801:Humans; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D059748:Proteolysis; D012097:Repressor Proteins / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054325:vpr Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D012097:Repressor Proteins; C549924:ZGPAT protein, human; D054325:vpr Gene Products, Human Immunodeficiency Virus; D044767:Ubiquitin-Protein Ligases; C530533:DCAF1 protein, human; D017346:Protein Serine-Threonine Kinases; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex