title: The Cleavage and Polyadenylation Specificity Factor 6 (CPSF6) Subunit of the Capsid-recruited Pre-messenger RNA Cleavage Factor I (CFIm) Complex Mediates HIV-1 Integration into Genes.
abstract: HIV-1 favors integration into active genes and gene-enriched regions of host cell chromosomes, thus maximizing the probability of provirus expression immediately after integration. This requires cleavage and polyadenylation specificity factor 6 (CPSF6), a cellular protein involved in pre-mRNA 3' end processing that binds HIV-1 capsid and connects HIV-1 preintegration complexes to intranuclear trafficking pathways that link integration to transcriptionally active chromatin. CPSF6 together with CPSF5 and CPSF7 are known subunits of the cleavage factor I (CFIm) 3' end processing complex; however, CPSF6 could participate in additional protein complexes. The molecular mechanisms underpinning the role of CPSF6 in HIV-1 infection remain to be defined. Here, we show that a majority of cellular CPSF6 is incorporated into the CFIm complex. HIV-1 capsid recruits CFIm in a CPSF6-dependent manner, which suggests that the CFIm complex mediates the known effects of CPSF6 in HIV-1 infection. To dissect the roles of CPSF6 and other CFIm complex subunits in HIV-1 infection, we analyzed virologic and integration site targeting properties of a CPSF6 variant with mutations that prevent its incorporation into CFIm We show, somewhat surprisingly, that CPSF6 incorporation into CFIm is not required for its ability to direct preferential HIV-1 integration into genes. The CPSF5 and CPSF7 subunits appear to have only a minor, if any, role in this process even though they appear to facilitate CPSF6 binding to capsid. Thus, CPSF6 alone controls the key molecular interactions that specify HIV-1 preintegration complex trafficking to active chromatin.
authors.affiliation: From the Department of Molecular Biology and Microbiology, Case Western Reserve School of Medicine, Cleveland, Ohio 44106 and.
authors.forename: Sheeba
authors.initials: S
authors.lastname: Rasheedi
authors.affiliation: From the Department of Molecular Biology and Microbiology, Case Western Reserve School of Medicine, Cleveland, Ohio 44106 and.
authors.forename: Ming-Chieh
authors.initials: MC
authors.lastname: Shun
authors.affiliation: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215.
authors.forename: Erik
authors.initials: E
authors.lastname: Serrao
authors.affiliation: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Sowd
authors.affiliation: From the Department of Molecular Biology and Microbiology, Case Western Reserve School of Medicine, Cleveland, Ohio 44106 and.
authors.forename: Juan
authors.initials: J
authors.lastname: Qian
authors.affiliation: From the Department of Molecular Biology and Microbiology, Case Western Reserve School of Medicine, Cleveland, Ohio 44106 and.
authors.forename: Caili
authors.initials: C
authors.lastname: Hao
authors.affiliation: From the Department of Molecular Biology and Microbiology, Case Western Reserve School of Medicine, Cleveland, Ohio 44106 and.
authors.forename: Twishasri
authors.initials: T
authors.lastname: Dasgupta
authors.affiliation: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215.
authors.forename: Alan N
authors.initials: AN
authors.lastname: Engelman
authors.affiliation: From the Department of Molecular Biology and Microbiology, Case Western Reserve School of Medicine, Cleveland, Ohio 44106 and jacek.skowronski@case.edu.
authors.forename: Jacek
authors.initials: J
authors.lastname: Skowronski
mesh_terms: D002213:Capsid / Q000378:metabolism*; D015658:HIV Infections / Q000235:genetics / Q000378:metabolism / Q000821:virology; D015497:HIV-1 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D012322:RNA Precursors / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D016662:Virus Integration; D039221:mRNA Cleavage and Polyadenylation Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D012322:RNA Precursors; D012333:RNA, Messenger; C450562:cleavage factor Im, human; D039221:mRNA Cleavage and Polyadenylation Factors
keywords: CFIm; CPSF6; RNA processing; capsid; human immunodeficiency virus (HIV); infection; integration; nuclear transport; protein complex