The Structure-Specific Recognition Protein 1 Associates with Lens Epithelium-Derived Growth Factor Proteins and Modulates HIV-1 Replication

Angelica P. Lopez, Jeffrey R. Kugelman, Jose Garcia-Rivera, Eduardo Urias, Sandra A. Salinas, Martin E Fernandez-Zapico, Manuel Llano

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2814-2831
Number of pages18
JournalJournal of Molecular Biology
Volume428
Issue number14
DOIs
StatePublished - Jul 17 2016

Fingerprint

HIV-1
Proteins
Chromatin
HIV Infections
lens epithelium-derived growth factor
Virus Integration
Murine Leukemia Viruses
Chromatin Assembly and Disassembly
Viral Genes
Viral DNA
Small Interfering RNA
Genome
Viruses
T-Lymphocytes
Gene Expression
Infection
Genes

Keywords

  • FACT complex
  • HIV-1 cofactor
  • HIV-1 replication
  • HMG domain
  • PWWP domain

ASJC Scopus subject areas

  • Molecular Biology

Cite this

The Structure-Specific Recognition Protein 1 Associates with Lens Epithelium-Derived Growth Factor Proteins and Modulates HIV-1 Replication. / Lopez, Angelica P.; Kugelman, Jeffrey R.; Garcia-Rivera, Jose; Urias, Eduardo; Salinas, Sandra A.; Fernandez-Zapico, Martin E; Llano, Manuel.

In: Journal of Molecular Biology, Vol. 428, No. 14, 17.07.2016, p. 2814-2831.

Research output: Contribution to journalArticle

Lopez, Angelica P. ; Kugelman, Jeffrey R. ; Garcia-Rivera, Jose ; Urias, Eduardo ; Salinas, Sandra A. ; Fernandez-Zapico, Martin E ; Llano, Manuel. / The Structure-Specific Recognition Protein 1 Associates with Lens Epithelium-Derived Growth Factor Proteins and Modulates HIV-1 Replication. In: Journal of Molecular Biology. 2016 ; Vol. 428, No. 14. pp. 2814-2831.
@article{95d9f27d36724c6c9074c5ab31b853f8,
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.",
keywords = "FACT complex, HIV-1 cofactor, HIV-1 replication, HMG domain, PWWP domain",
author = "Lopez, {Angelica P.} and Kugelman, {Jeffrey R.} and Jose Garcia-Rivera and Eduardo Urias and Salinas, {Sandra A.} and Fernandez-Zapico, {Martin E} and Manuel Llano",
year = "2016",
month = "7",
day = "17",
doi = "10.1016/j.jmb.2016.05.013",
language = "English (US)",
volume = "428",
pages = "2814--2831",
journal = "Journal of Molecular Biology",
issn = "0022-2836",
publisher = "Academic Press Inc.",
number = "14",

}

TY - JOUR

T1 - The Structure-Specific Recognition Protein 1 Associates with Lens Epithelium-Derived Growth Factor Proteins and Modulates HIV-1 Replication

AU - Lopez, Angelica P.

AU - Kugelman, Jeffrey R.

AU - Garcia-Rivera, Jose

AU - Urias, Eduardo

AU - Salinas, Sandra A.

AU - Fernandez-Zapico, Martin E

AU - Llano, Manuel

PY - 2016/7/17

Y1 - 2016/7/17

N2 - 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.

AB - 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.

KW - FACT complex

KW - HIV-1 cofactor

KW - HIV-1 replication

KW - HMG domain

KW - PWWP domain

UR - http://www.scopus.com/inward/record.url?scp=84971634962&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84971634962&partnerID=8YFLogxK

U2 - 10.1016/j.jmb.2016.05.013

DO - 10.1016/j.jmb.2016.05.013

M3 - Article

C2 - 27216501

AN - SCOPUS:84971634962

VL - 428

SP - 2814

EP - 2831

JO - Journal of Molecular Biology

JF - Journal of Molecular Biology

SN - 0022-2836

IS - 14

ER -