LEDGF/p75 Proteins with Alternative Chromatin Tethers Are Functional HIV-1 Cofactors

PLoS Pathogens

Manuel Llano¹  Jose A. Garcia-Rivera¹  James H. Morrison²  Mary Peretz²  Dyana T. Saenz²  Anne M. Meehan²  Eric M. Poeschla² 

[1] Biological Sciences Department, University of Texas, El Paso, Texas, United States of America;Department of Molecular Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota, United States of America

关键词: Chromatin;    HIV-1;    Histones;    Nucleosomes;    Cofactors (biochemistry);    RNA interference;    DNA-binding proteins;    Cell cycle;    cell division;   

DOI  :  10.1371/journal.ppat.1000522

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY