Zinc chelation inhibits HIV Vif activity and liberates antiviral function of the cytidine deaminase APOBEC3G

被引：79

作者：

Xiao, Zuoxiang

Ehrlich, Elana

Luo, Kun

Xiong, Yong

Yu, Xiao-Fang

机构：

[1] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD 21205 USA

[2] Zhejiang Univ, Sch Med, Affiliated Hosp 2, Zhejiang, Peoples R China

来源：

FASEB JOURNAL | 2007年 / 21卷 / 01期

关键词：

HIV-1; virion; lentiviral Vif proteins; TPEN; zinc binding motif;

D O I：

10.1096/fj.06-6773com

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 membranepermeable 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 mu M 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.

引用

收藏

页码：217 / 222

页数：6

相关论文

共 29 条

[1] Intrinsic immunity: a front-line defense against viral attack [J].

Bieniasz, PD .

NATURE IMMUNOLOGY, 2004, 5 (11) :1109-1115

[2] Genetic analysis of a potential zinc-binding domain of the adenovirus E4 34k protein [J].

Boyer, JL ;

Ketner, G .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (20) :14969-14978

[3] Mammalian mediator subunit mMED8 is an Elongin BC-interacting protein that can assemble with Cul2 and Rbx1 to reconstitute a ubiquitin ligase [J].

Brower, CS ;

Sato, S ;

Tomomori-Sato, C ;

Kamura, T ;

Pause, A ;

Stearman, R ;

Klausner, RD ;

Malik, S ;

Lane, WS ;

Sorokina, I ;

Roeder, RG ;

Conaway, JW ;

Conaway, RC .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2002, 99 (16) :10353-10358

[4] Human immunodeficiency virus type 1 coreceptors participate in postentry stages in the virus replication cycle and function in simian immunodeficiency virus infection [J].

Chackerian, B ;

Long, EM ;

Luciw, PA ;

Overbaugh, J .

JOURNAL OF VIROLOGY, 1997, 71 (05) :3932-3939

[5] The Vif protein of HIV triggers degradation of the human antiretroviral DNA deaminase APOBEC3G [J].

Conticello, SG ;

Harris, RS ;

Neuberger, MS .

CURRENT BIOLOGY, 2003, 13 (22) :2009-2013

[6] Death by deamination: A novel host restriction system for HIV-1 [J].

Goff, SP .

CELL, 2003, 114 (03) :281-283

[7] Retroviral restriction by APOBEC proteins [J].

Harris, RS ;

Liddament, MT .

NATURE REVIEWS IMMUNOLOGY, 2004, 4 (11) :868-877

[8] VHL-box and SOCS-box domains determine binding specificity for Cul2-Rbx1 and Cul5-Rbx2 modules of ubiquitin ligases [J].

Kamura, T ;

Maenaka, K ;

Kotoshiba, S ;

Matsumoto, M ;

Kohda, D ;

Conaway, RC ;

Conaway, JW ;

Nakayama, KI .

GENES & DEVELOPMENT, 2004, 18 (24) :3055-3065

[9] The Elongin BC complex interacts with the conserved SOCS-box motif present in members of the SOCS, ras, WD-40 repeat, and ankyrin repeat families [J].

Kamura, T ;

Sato, S ;

Haque, D ;

Liu, L ;

Kaelin, WG ;

Conaway, RC ;

Conaway, JW .

GENES & DEVELOPMENT, 1998, 12 (24) :3872-3881

[10] MUF1, a novel Elongin BC-interacting leucine-rich repeat protein that can assemble with Cul5 and Rbx1 to reconstitute a ubiquitin ligase [J].

Kamura, T ;

Burian, D ;

Yan, Q ;

Schmidt, SL ;

Lane, WS ;

Querido, E ;

Branton, PE ;

Shilatifard, A ;

Conaway, RC ;

Conaway, JW .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (32) :29748-29753