title: The Structure-Specific Recognition Protein 1 Associates with Lens Epithelium-Derived Growth Factor Proteins and Modulates HIV-1 Replication.
abstract: The lens epithelium-derived growth factor p75 (LEDGF/p75) is a chromatin-bound protein essential for efficient lentiviral integration. Genome-wide studies have located LEDGF/p75 inside actively transcribed genes where it mediates lentiviral integration. Although its role in HIV-1 integration is clearly established, the role of LEDGF/p75-associated proteins in HIV-1 infection remains unexplored. Using protein-protein interaction assays, we demonstrated that LEDGF/p75 complexes with a chromatin-remodeling complex facilitates chromatin transcription (FACT), a heterodimer of the structure-specific recognition protein 1 (SSRP1) and the human homolog of suppressor of Ty 16 (hSpt16). Detailed analysis of the interaction of LEDGF/p75 with the FACT complex indicates that LEDGF/p75 interacts with SSRP1 in an hSpt16-independent manner that requires the PWWP domain of LEDGF proteins and the HMG domain of SSRP1. Functional characterizations demonstrate a LEDGF/p75-independent role of SSRP1 in the regulation of HIV-1 replication. shRNA-mediated partial knockdown of SSRP1 reduces HIV-1 infection, but not Murine Leukemia Virus, in human CD4(+) T cells. Similarly, SSRP1 knockdown affects infection by HIV-1-derived viruses that express genes from the viral LTR but not from an internal immediate-early CMV promoter, suggesting a role of SSRP1 in LTR-driven gene expression but not in viral DNA integration. Together, our data demonstrate for the first time the association of LEDGF proteins with the FACT complex and give further support to a role of SSRP1 in HIV-1 infection.
authors.affiliation: Department of Biological Sciences, University of Texas at El Paso, El Paso, TX 79968, USA.
authors.forename: Angelica P
authors.initials: AP
authors.lastname: Lopez
authors.affiliation: Department of Biological Sciences, University of Texas at El Paso, El Paso, TX 79968, USA.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Kugelman
authors.affiliation: Department of Biological Sciences, University of Texas at El Paso, El Paso, TX 79968, USA.
authors.forename: Jose
authors.initials: J
authors.lastname: Garcia-Rivera
authors.affiliation: Department of Biological Sciences, University of Texas at El Paso, El Paso, TX 79968, USA.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Urias
authors.affiliation: Department of Biological Sciences, University of Texas at El Paso, El Paso, TX 79968, USA.
authors.forename: Sandra A
authors.initials: SA
authors.lastname: Salinas
authors.affiliation: Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, MN 55905, USA. Electronic address: fernandezzapico.martin@mayo.edu.
authors.forename: Martin E
authors.initials: ME
authors.lastname: Fernandez-Zapico
authors.affiliation: Department of Biological Sciences, University of Texas at El Paso, El Paso, TX 79968, USA. Electronic address: mllano@utep.edu.
authors.forename: Manuel
authors.initials: M
authors.lastname: Llano
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism; D004261:DNA Replication / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D057809:HEK293 Cells; D019427:HIV Integrase / Q000378:metabolism; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism; D006609:High Mobility Group Proteins / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D035602:Transcriptional Elongation Factors / Q000378:metabolism*; D016662:Virus Integration / Q000502:physiology; D014779:Virus Replication / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002843:Chromatin; D004268:DNA-Binding Proteins; D006609:High Mobility Group Proteins; D036341:Intercellular Signaling Peptides and Proteins; C504649:PSIP1 protein, human; C073537:SSRP1 protein, human; D014157:Transcription Factors; D035602:Transcriptional Elongation Factors; C119380:lens epithelium-derived growth factor; D019427:HIV Integrase
keywords: FACT complex; HIV-1 cofactor; HIV-1 replication; HMG domain; PWWP domain