Modulation of chromatin structure by the FACT histone chaperone complex regulates HIV-1 integration
Julien Matysiak,
Paul Lesbats,
Eric Mauro,
Delphine Lapaillerie,
Jean-William Dupuy,
Angelica P. Lopez,
Mohamed Salah Benleulmi,
Christina Calmels,
Marie-Line Andreola,
Marc Ruff,
Manuel Llano,
Olivier Delelis,
Marc Lavigne,
Vincent Parissi
Affiliations
Julien Matysiak
Fundamental Microbiology and Pathogenicity Laboratory, UMR 5234 CNRS, University of Bordeaux, SFR TransBioMed
Paul Lesbats
Fundamental Microbiology and Pathogenicity Laboratory, UMR 5234 CNRS, University of Bordeaux, SFR TransBioMed
Eric Mauro
Fundamental Microbiology and Pathogenicity Laboratory, UMR 5234 CNRS, University of Bordeaux, SFR TransBioMed
Delphine Lapaillerie
Fundamental Microbiology and Pathogenicity Laboratory, UMR 5234 CNRS, University of Bordeaux, SFR TransBioMed
Jean-William Dupuy
Centre Génomique fonctionnelle Bordeaux, Plateforme Proteome, Université de Bordeaux
Angelica P. Lopez
Department of Biological Sciences, University of Texas at El Paso
Mohamed Salah Benleulmi
Fundamental Microbiology and Pathogenicity Laboratory, UMR 5234 CNRS, University of Bordeaux, SFR TransBioMed
Christina Calmels
Fundamental Microbiology and Pathogenicity Laboratory, UMR 5234 CNRS, University of Bordeaux, SFR TransBioMed
Marie-Line Andreola
Fundamental Microbiology and Pathogenicity Laboratory, UMR 5234 CNRS, University of Bordeaux, SFR TransBioMed
Marc Ruff
Département de Biologie Structurale Intégrative, UDS, U596 INSERM, UMR7104 CNRS, IGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire)
Manuel Llano
Department of Biological Sciences, University of Texas at El Paso
Olivier Delelis
LBPA, UMR8113, CNRS, ENS-Cachan
Marc Lavigne
Department of Virology, UMR 3569, CNRS, Institut Pasteur
Vincent Parissi
Fundamental Microbiology and Pathogenicity Laboratory, UMR 5234 CNRS, University of Bordeaux, SFR TransBioMed
Abstract Background Insertion of retroviral genome DNA occurs in the chromatin of the host cell. This step is modulated by chromatin structure as nucleosomes compaction was shown to prevent HIV-1 integration and chromatin remodeling has been reported to affect integration efficiency. LEDGF/p75-mediated targeting of the integration complex toward RNA polymerase II (polII) transcribed regions ensures optimal access to dynamic regions that are suitable for integration. Consequently, we have investigated the involvement of polII-associated factors in the regulation of HIV-1 integration. Results Using a pull down approach coupled with mass spectrometry, we have selected the FACT (FAcilitates Chromatin Transcription) complex as a new potential cofactor of HIV-1 integration. FACT is a histone chaperone complex associated with the polII transcription machinery and recently shown to bind LEDGF/p75. We report here that a tripartite complex can be formed between HIV-1 integrase, LEDGF/p75 and FACT in vitro and in cells. Biochemical analyzes show that FACT-dependent nucleosome disassembly promotes HIV-1 integration into chromatinized templates, and generates highly favored nucleosomal structures in vitro. This effect was found to be amplified by LEDGF/p75. Promotion of this FACT-mediated chromatin remodeling in cells both increases chromatin accessibility and stimulates HIV-1 infectivity and integration. Conclusions Altogether, our data indicate that FACT regulates HIV-1 integration by inducing local nucleosomes dissociation that modulates the functional association between the incoming intasome and the targeted nucleosome.
