Zinc chelation inhibits HIV Vif activity and liberates antiviral function of the cytidine deaminase APOBEC3G.
APOBEC3 proteins are cellular antiviral proteins that are targeted for proteasomal degradation by primate lentiviral Vif proteins. Vif acts as a substrate receptor for the Cullin5 (Cul5) E3 ubiquitin ligase, specifically interacting with Cul5 through a novel H-(x5)-C-(x17-18)-C-(x3-5)-H zinc binding motif. Using the membrane-permeable zinc chelator, N,N,N',N'-tetrakis-(2-pyridylmethyl) ethylenediamine (TPEN), we demonstrated a requirement for zinc for Vif function in vivo. Treatment with TPEN at an IC50 of 1.79 microM inhibits Cul5 recruitment and APOBEC3G (A3G) degradation. Zinc chelation prevented Vif function in infectivity assays, allowing the virus to become sensitive to the antiviral activity of A3G. Zinc chelation had no effect on cellular Cul5-SOCS3 E3 ligase assembly, suggesting that zinc-dependent E3 ligase assembly may be unique to HIV-1 Vif, representing a new target for novel drug design.
Xiao
Zuoxiang
Z
Department of Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe St., Baltimore, MD 21205, USA.
Ehrlich
Elana
E
Luo
Kun
K
Xiong
Yong
Y
Yu
Xiao-Fang
XF
D000071480:APOBEC-3G Deaminase; D002460:Cell Line; D002614:Chelating Agents / Q000737:chemistry / Q000494:pharmacology*; D044842:Cullin Proteins / Q000378:metabolism; D003564:Cytidine Deaminase; D005029:Ethylenediamines / Q000494:pharmacology; D016346:Gene Products, vif / Q000037:antagonists & inhibitors*; D006801:Humans; D006868:Hydrolysis; D009700:Nucleoside Deaminases / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D038301:Virus Inactivation; D015032:Zinc / Q000737:chemistry*
C496871:CUL5 protein, human; D002614:Chelating Agents; D044842:Cullin Proteins; D005029:Ethylenediamines; D016346:Gene Products, vif; D012097:Repressor Proteins; D009700:Nucleoside Deaminases; D000071480:APOBEC-3G Deaminase; C464924:APOBEC3G protein, human; D003564:Cytidine Deaminase; D015032:Zinc; C044387:N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine