HIV-1 replication through hHR23A-mediated interaction of Vpr with 26S proteasome.
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.
Li
Ge
G
Department of Pathology, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
Elder
Robert T
RT
Dubrovsky
Larisa
L
Liang
Dong
D
Pushkarsky
Tatiana
T
Chiu
Karen
K
Fan
Tao
T
Sire
Josephine
J
Bukrinsky
Michael
M
Zhao
Richard Y
RY
D002460:Cell Line; D045643:DNA Repair Enzymes / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000502:physiology*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D014779:Virus Replication; D054325:vpr Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
D004268:DNA-Binding Proteins; D054325:vpr Gene Products, Human Immunodeficiency Virus; C514912:vpr protein, Human immunodeficiency virus 1; C086985:RAD23A protein, human; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; D045643:DNA Repair Enzymes