Human immunodeficiency virus type 1 Vpr induces the degradation of the UNG and SMUG uracil-DNA glycosylases
Human immunodeficiency virus type 1 Vpr induces the degradation of the UNG and SMUG uracil-DNA glycosylases
复制标题
DOI：
10.1128/jvi.79.17.10978-10987.2005
复制
发表时间：
2005-09-01
影响因子：
5.4
通讯作者：
Landau, NR
中科院分区：
文献类型：
--
作者：
Schröfelbauer, B;Yu, Q;Landau, NR
人类免疫缺陷病毒 1 型 (HIV-1) 辅助蛋白 Vpr 先前已被证明可与细胞尿嘧啶 DNA 糖基化酶 UNG 结合。我们在此表明，Vpr 与 UNG 和相关酶 SMUG 的结合会诱导它们的蛋白酶体降解。 UNG 和 SMUG 被发现存在于 Delta vpr HIV-1 病毒体中，但在 vpr(+) 病毒体中含量明显较低。 Delta vpr 病毒粒子含有易于检测的尿嘧啶-DNA 糖基化酶活性，而 vpr(+) 病毒粒子的活性降低至不可检测的水平。与蛋白酶体降解一致，在细胞裂解物中检测到含有 Vpr 和 E3 泛素连接酶成分 Cull 和 Cul4 的复合物。我们假设Vpr的相互作用可能是病毒降低病毒逆转录物中尿嘧啶残基脱碱基位点频率的一种手段，这是由APOBEC3催化的胞嘧啶残基脱氨基引起的。尽管 APOBEC3 很大程度上被 Vif 辅助蛋白中和，但残留的酶可能保留在病毒颗粒中，从而产生尿嘧啶。为了支持这一点，在有限量的 APOBEC3G 存在下产生的 Delta vif vpr+ HIV-1 明显比 Delta vif Delta vpr 病毒更具传染性。此外，vpr(+) HIV-1 在表达有限量 APOBEC3G 的细胞中比 vpr(-) 病毒复制更有效。这些发现强调了胞苷脱氨基在病毒复制周期中的重要性，并提出了 Vpr 的新功能。
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 Delta vpr HIV-1 virions but were significantly less abundant in vpr(+) virions. Delta vpr 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 Cull 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, Delta vif vpr+ HIV-1 produced in the presence of limited amounts of APOBEC3G was significantly more infectious than Delta vif Delta vpr 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.