First Hospital of Jilin University, Institute of Virology and AIDS Research, Changchun, Jilin Province 130021, China.
Nature. 2011 Dec 21;481(7381):376-9. doi: 10.1038/nature10718.
The human APOBEC3 cytidine deaminases are potent inhibitors of diverse retroviruses, including human immunodeficiency virus-1 (HIV-1). HIV-1 Vif forms an E3 ubiquitin ligase complex with cullin 5 (CUL5), elongin B and elongin C , which promotes the polyubiquitination and degradation of APOBEC3 substrates. Here we demonstrate in human T cells that core binding factor β (CBF-β) is a key regulator of the evasion of HIV-1 from the host defence mediated by APOBEC3. CBF-β, the non-DNA-binding subunit of a heterodimeric transcription factor, regulates the folding and DNA-binding activity of partner RUNX family proteins, which have important roles in the development and differentiation of diverse cell types, including T lymphocytes. In our study, knockdown of endogenous CBF-β blocked Vif-induced APOBEC3G polyubiquitination and degradation. CBF-β was not required for the interaction between Vif and APOBEC3G, yet was essential for the assembly of the Vif-CUL5 E3-ubiquitin-ligase complex. CBF-β proved to be a unique regulator of primate lentiviral Vif and not a general component of the CUL5 E3 ubiquitin ligase. We show that Vif and CBF-β physically interact, and that the amino-terminal region of Vif is required for this interaction. Furthermore, interactions with Vif required regions in CBF-β that are not involved in RUNX protein binding. Considering the importance of the interaction between Vif and CBF-β, disrupting this interaction represents an attractive pharmacological intervention against HIV-1.
人类 APOBEC3 胞嘧啶脱氨酶是多种逆转录病毒（包括人类免疫缺陷病毒-1（HIV-1））的有效抑制剂。HIV-1 Vif 与 CUL5、 elongin B 和 elongin C 形成 E3 泛素连接酶复合物，促进 APOBEC3 底物的多泛素化和降解。在这里，我们在人类 T 细胞中证明，核心结合因子 β（CBF-β）是 HIV-1 逃避 APOBEC3 介导的宿主防御的关键调节剂。CBF-β是一种异二聚体转录因子的非 DNA 结合亚基，调节其伴侣 RUNX 家族蛋白的折叠和 DNA 结合活性，后者在包括 T 淋巴细胞在内的多种细胞类型的发育和分化中发挥重要作用。在我们的研究中，内源性 CBF-β 的敲低阻止了 Vif 诱导的 APOBEC3G 多泛素化和降解。CBF-β 对于 Vif 和 APOBEC3G 之间的相互作用不是必需的，但对于 Vif-CUL5 E3 泛素连接酶复合物的组装是必需的。CBF-β 被证明是灵长类慢病毒 Vif 的独特调节剂，而不是 CUL5 E3 泛素连接酶的一般组成部分。我们表明 Vif 和 CBF-β 相互作用，并且 Vif 的氨基末端区域是这种相互作用所必需的。此外，与 Vif 的相互作用需要 CBF-β 中不涉及 RUNX 蛋白结合的区域。考虑到 Vif 和 CBF-β 之间相互作用的重要性，破坏这种相互作用代表了一种有吸引力的抗 HIV-1 药理学干预。
