HIV-1 replication through hHR23A-mediated interaction of Vpr with 26S proteasome

• Published in: PloS one 2010-06, Vol.5 (6), p.e11371-e11371
• Main Authors: Li, Ge, Elder, Robert T, Dubrovsky, Larisa, Liang, Dong, Pushkarsky, Tatiana, Chiu, Karen, Fan, Tao, Sire, Josephine, Bukrinsky, Michael, Zhao, Richard Y
• Format: Article
• Language: English
• Subjects: Biodegradation; CCR5 protein; Cell cycle; Cell growth; Cell Line; Cells (Biology); Children & youth; Deoxyribonucleic acid; Development and progression; DNA; DNA repair; DNA Repair Enzymes - physiology; DNA-Binding Proteins - physiology; Fission; Gene expression; Health aspects; HIV; HIV-1 - physiology; Human immunodeficiency virus; Human immunodeficiency virus 1; Humans; Immunology; Infection; Infections; Lymphocytes; Lymphocytes T; Macrophages; Mammalian cells; Mammals; Medicine; Mutation; Pathogenesis; Pathology; Phosphorylation; Proteasome 26S; Proteasome Endopeptidase Complex - chemistry; Proteasome Endopeptidase Complex - metabolism; Protein Binding; Proteins; Replication; RNA-mediated interference; Schizosaccharomyces pombe; T cells; Ubiquitin; Ubiquitination; Virions; Virology; Virology/Effects of Virus Infection on Host Gene Expression; Virology/Immunodeficiency Viruses; Virus diseases; Virus Replication; vpr Gene Products, Human Immunodeficiency Virus - metabolism; Vpr protein; Yeast
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0011371

HIV-1 Vpr is a virion-associated protein. Its activities link to viral pathogenesis and disease progression of HIV-infected patients. In vitro, Vpr moderately activates HIV-1 replication in proliferating T cells, but it is required for efficient viral infection and replication in vivo in non-dividing cells such as macrophages. How exactly Vpr contributes to viral replication remains elusive. We show here that Vpr stimulates HIV-1 replication at least in part through its interaction with hHR23A, a protein that binds to 19S subunit of the 26S proteasome and shuttles ubiquitinated proteins to the proteasome for degradation. The Vpr-proteasome interaction was initially discovered in fission yeast, where Vpr was shown to associate with Mts4 and Mts2, two 19S-associated proteins. The interaction of Vpr with the 19S subunit of the proteasome was further confirmed in mammalian cells where Vpr associates with the mammalian orthologues of fission yeast Mts4 and S5a. Consistently, depletion of hHR23A interrupts interaction of Vpr with proteasome in mammalian cells. Furthermore, Vpr promotes hHR23A-mediated protein-ubiquitination, and down-regulation of hHR23A using RNAi significantly reduced viral replication in non-proliferating MAGI-CCR5 cells and primary macrophages. These findings suggest that Vpr-proteasome interaction might counteract certain host restriction factor(s) to stimulate viral replication in non-dividing cells.