HIV-1 Vpr degrades the HLTF DNA translocase in T cells and macrophages.
Viruses often interfere with the DNA damage response to better replicate in their hosts. The human immunodeficiency virus 1 (HIV-1) viral protein R (Vpr) protein has been reported to modulate the activity of the DNA repair structure-specific endonuclease subunit (SLX4) complex and to promote cell cycle arrest. Vpr also interferes with the base-excision repair pathway by antagonizing the uracil DNA glycosylase (Ung2) enzyme. Using an unbiased quantitative proteomic screen, we report that Vpr down-regulates helicase-like transcription factor (HLTF), a DNA translocase involved in the repair of damaged replication forks. Vpr subverts the DDB1-cullin4-associated-factor 1 (DCAF1) adaptor of the Cul4A ubiquitin ligase to trigger proteasomal degradation of HLTF. This event takes place rapidly after Vpr delivery to cells, before and independently of Vpr-mediated G2 arrest. HLTF is degraded in lymphocytic cells and macrophages infected with Vpr-expressing HIV-1. Our results reveal a previously unidentified strategy for HIV-1 to antagonize DNA repair in host cells.
INSERM, U1016, Institut Cochin, Paris 75014, France; CNRS, UMR8104, Paris 75014, France; Department of Infectiology and Microbiology, Université Paris Descartes, Sorbonne Paris Cité, Paris 75014, France;
Hichem
H
Lahouassa
INSERM, U1016, Institut Cochin, Paris 75014, France; CNRS, UMR8104, Paris 75014, France; Department of Infectiology and Microbiology, Université Paris Descartes, Sorbonne Paris Cité, Paris 75014, France;
Marie-Lise
ML
Blondot
Department of Virology, Virus & Immunity Unit, Institut Pasteur, Paris 75015, France; CNRS Unité de Recherche Associée 3015, Paris 75015, France;
Lise
L
Chauveau
INSERM, U1016, Institut Cochin, Paris 75014, France; CNRS, UMR8104, Paris 75014, France; Department of Infectiology and Microbiology, Université Paris Descartes, Sorbonne Paris Cité, Paris 75014, France;
Ghina
G
Chougui
INSERM, U1016, Institut Cochin, Paris 75014, France; CNRS, UMR8104, Paris 75014, France; Department of Infectiology and Microbiology, Université Paris Descartes, Sorbonne Paris Cité, Paris 75014, France;
Marina
M
Morel
INSERM, U1016, Institut Cochin, Paris 75014, France; CNRS, UMR8104, Paris 75014, France; Department of Infectiology and Microbiology, Université Paris Descartes, Sorbonne Paris Cité, Paris 75014, France; 3P5 Proteomic Facility, Paris Descartes University, Paris 75014, France;
Marjorie
M
Leduc
INSERM, U1016, Institut Cochin, Paris 75014, France; CNRS, UMR8104, Paris 75014, France; Department of Infectiology and Microbiology, Université Paris Descartes, Sorbonne Paris Cité, Paris 75014, France; 3P5 Proteomic Facility, Paris Descartes University, Paris 75014, France;
François
F
Guillonneau
INSERM, U1016, Institut Cochin, Paris 75014, France; CNRS, UMR8104, Paris 75014, France; Department of Infectiology and Microbiology, Université Paris Descartes, Sorbonne Paris Cité, Paris 75014, France;
Bertha Cecilia
BC
Ramirez
Department of Virology, Virus & Immunity Unit, Institut Pasteur, Paris 75015, France; CNRS Unité de Recherche Associée 3015, Paris 75015, France; Vaccine Research Institute, Creteil 94010, France.
Olivier
O
Schwartz
INSERM, U1016, Institut Cochin, Paris 75014, France; CNRS, UMR8104, Paris 75014, France; Department of Infectiology and Microbiology, Université Paris Descartes, Sorbonne Paris Cité, Paris 75014, France; florence.margottin-goguet@inserm.fr.
Florence
F
Margottin-Goguet
D002478:Cells, Cultured; D004249:DNA Damage / Q000502:physiology*; D004260:DNA Repair / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008264:Macrophages / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D054325:vpr Gene Products, Human Immunodeficiency Virus
D004268:DNA-Binding Proteins; C100023:HLTF protein, human; D014157:Transcription Factors; D054325:vpr Gene Products, Human Immunodeficiency Virus; C514912:vpr protein, Human immunodeficiency virus 1
DNA repair; HIV; SILAC; Vpr target; restriction factor