Human immunodeficiency virus type 1 Vpr induces the degradation of the UNG and SMUG uracil-DNA glycosylases.
The human immunodeficiency virus type 1 (HIV-1) accessory protein Vpr has previously been shown to bind to the cellular uracil DNA glycosylase UNG. We show here that the binding of Vpr to UNG and to the related enzyme SMUG induces their proteasomal degradation. UNG and SMUG were found to be encapsidated in Deltavpr HIV-1 virions but were significantly less abundant in vpr(+) virions. Deltavpr virions contained readily detectable uracil-DNA glycosylase enzymatic activity, while the activity was reduced to undetectable levels in vpr(+) virions. Consistent with proteasomal degradation, complexes that contained Vpr and the E3 ubiquitin ligase components Cul1 and Cul4 were detected in cell lysates. We hypothesized that the interaction of Vpr might be a means for the virus to reduce the frequency of abasic sites in viral reverse transcripts at uracil residues caused by APOBEC3-catalyzed deamination of cytosine residues. Although APOBEC3 is largely neutralized by the Vif accessory protein, residual enzyme could remain in virions that would generate uracils. In support of this, Deltavif vpr(+) HIV-1 produced in the presence of limited amounts of APOBEC3G was significantly more infectious than Deltavif Deltavpr virus. In Addition, vpr(+) HIV-1 replicated more efficiently than vpr(-) virus in cells that expressed limited amounts of APOBEC3G. The findings highlight the importance of cytidine deamination in the virus replication cycle and present a novel function for Vpr.
Schröfelbauer
Bärbel
B
Infectious Disease Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
Yu
Qin
Q
Zeitlin
Samantha G
SG
Landau
Nathaniel R
NR
D000071480:APOBEC-3G Deaminase; D002460:Cell Line; D003564:Cytidine Deaminase; D045647:DNA Glycosylases / Q000378:metabolism*; D016336:Gene Products, vpr / Q000378:metabolism*; D015497:HIV-1 / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D009700:Nucleoside Deaminases; D010446:Peptide Fragments / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism; D012097:Repressor Proteins; D051981:Uracil-DNA Glycosidase; D014779:Virus Replication; D054325:vpr Gene Products, Human Immunodeficiency Virus
D016336:Gene Products, vpr; D010446:Peptide Fragments; D011506:Proteins; D012097:Repressor Proteins; D054325:vpr Gene Products, Human Immunodeficiency Virus; C422457:vpr peptide (13-33), Human immunodeficiency virus 1; D045647:DNA Glycosylases; D051981:Uracil-DNA Glycosidase; D046988:Proteasome Endopeptidase Complex; D009700:Nucleoside Deaminases; D000071480:APOBEC-3G Deaminase; C464924:APOBEC3G protein, human; D003564:Cytidine Deaminase