LEDGF/p75 proteins with alternative chromatin tethers are functional HIV-1 cofactors

Anne M. Meehan, Dyana T. Saenz, James H. Morrison, Jose A. Garcia-Rivera, Mary Peretz, Manuel Llano, Eric M. Poeschla

Research output: Contribution to journalArticle

55 Scopus citations

Abstract

LEDGF/p75 can tether over-expressed lentiviral integrase proteins to chromatin but how this underlies its integration cofactor role for these retroviruses is unclear. While a single integrase binding domain (IBD) binds integrase, a complex N-terminal domain ensemble (NDE) interacts with unknown chromatin ligands. Whether integration requires chromatin tethering per se, specific NDE-chromatin ligand interactions or other emergent properties of LEDGF/p75 has been elusive. Here we replaced the NDE with strongly divergent chromatin-binding modules. The chimeras rescued integrase tethering and HIV-1 integration in LEDGF/p75-deficient cells. Furthermore, chromatin ligands could reside inside or outside the nucleosome core, and could be protein or DNA. Remarkably, a short Kaposi's sarcoma virus peptide that binds the histone 2A/B dimer converted GFP-IBD from an integration blocker to an integration cofactor that rescues over two logs of infectivity. NDE mutants were corroborative. Chromatin tethering per se is a basic HIV-1 requirement and this rather than engagement of particular chromatin ligands is important for the LEDGF/p75 cofactor mechanism.

Original languageEnglish (US)
Article numbere1000522
JournalPLoS pathogens
Volume5
Issue number7
DOIs
StatePublished - Jul 2009

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

Fingerprint Dive into the research topics of 'LEDGF/p75 proteins with alternative chromatin tethers are functional HIV-1 cofactors'. Together they form a unique fingerprint.

  • Cite this

    Meehan, A. M., Saenz, D. T., Morrison, J. H., Garcia-Rivera, J. A., Peretz, M., Llano, M., & Poeschla, E. M. (2009). LEDGF/p75 proteins with alternative chromatin tethers are functional HIV-1 cofactors. PLoS pathogens, 5(7), [e1000522]. https://doi.org/10.1371/journal.ppat.1000522