The HIV1 protein Vpr acts to promote G2 cell cycle arrest by engaging a DDB1 and Cullin4A-containing ubiquitin ligase complex using VprBP/DCAF1 as an adaptor.
The roles of the HIV1 protein Vpr in virus replication and pathogenesis remain unclear. Expression of Vpr in dividing cells causes cell cycle arrest in G(2). Vpr also facilitates low titer infection of terminally differentiated macrophages, enhances transcription, promotes apoptosis, and targets cellular uracil N-glycosylase for degradation. Using co-immunoprecipitation and tandem mass spectroscopy, we found that HIV1 Vpr engages a DDB1- and cullin4A-containing ubiquitin-ligase complex through VprBP/DCAF1. HIV2 Vpr has two Vpr-like proteins, Vpr and Vpx, which cause G(2) arrest and facilitate macrophage infection, respectively. HIV2 Vpr, but not Vpx, engages the same set of proteins. We further demonstrate that the interaction between Vpr and the ubiquitin-ligase components as well as further assembly of the ubiquitin-ligase are necessary for Vpr-mediated G(2) arrest. Our data support a model in which Vpr engages the ubiquitin ligase to deplete a cellular factor that is required for cell cycle progression into mitosis. Vpr, thus, functions like the HIV1 proteins Vif and Vpu to usurp cellular ubiquitin ligases for viral functions.
Wen
Xiaoyun
X
Center for Immunology and Microbial Disease, Albany Medical College, Albany, New York 12208.
Duus
Karen M
KM
Center for Immunology and Microbial Disease, Albany Medical College, Albany, New York 12208.
Friedrich
Thomas D
TD
Center for Immunology and Microbial Disease, Albany Medical College, Albany, New York 12208.
de Noronha
Carlos M C
CMC
Center for Immunology and Microbial Disease, Albany Medical College, Albany, New York 12208. Electronic address: DeNoroC@mail.AMC.edu.
D002352:Carrier Proteins / Q000502:physiology*; D002478:Cells, Cultured; D044842:Cullin Proteins / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000502:physiology*; D016195:G2 Phase; D016336:Gene Products, vpr / Q000502:physiology*; D006801:Humans; D047468:Immunoprecipitation; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*; D051981:Uracil-DNA Glycosidase / Q000378:metabolism
C114234:CUL4A protein, human; D002352:Carrier Proteins; D044842:Cullin Proteins; C091435:DDB1 protein, human; D004268:DNA-Binding Proteins; D016336:Gene Products, vpr; D044767:Ubiquitin-Protein Ligases; D051981:Uracil-DNA Glycosidase