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Proc Natl Acad Sci U S A. 2016 May 10;113(19):5311-6. doi: 10.1073/pnas.1600485113. Epub 2016 Apr 25.

HIV-1 Vpr degrades the HLTF DNA translocase in T cells and macrophages.

Author information

1
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;
2
Department of Virology, Virus & Immunity Unit, Institut Pasteur, Paris 75015, France; CNRS Unité de Recherche Associée 3015, Paris 75015, France;
3
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;
4
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.
5
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.

Abstract

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.

KEYWORDS:

DNA repair; HIV; SILAC; Vpr target; restriction factor

PMID:
27114546
PMCID:
PMC4868422
DOI:
10.1073/pnas.1600485113
[Indexed for MEDLINE]
Free PMC Article

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