HIV Type 1 Viral Infectivity Factor and the RUNX Transcription Factors Interact with Core Binding Factor β on Genetically Distinct Surfaces
HIV Type 1 Viral Infectivity Factor and the RUNX Transcription Factors Interact with Core Binding Factor β on Genetically Distinct Surfaces
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DOI：
10.1089/aid.2012.0142
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发表时间：
2012-12-01
影响因子：
1.5
通讯作者：
Harris, Reuben S.
中科院分区：
文献类型：
--
作者：
Hultquist, Judd F.;McDougle, Rebecca M.;Harris, Reuben S.
人类免疫缺陷病毒1型（HIV-1）需要细胞转录因子核心结合因子β亚基（CBF β）来稳定其病毒感染因子（Vif）蛋白并中和APOBEC 3限制因子。CBF β通常与RUNX家族的转录因子异源二聚化，增强其稳定性和DNA结合亲和力。为了测试Vif可能作为RUNX模拟物结合CBF β的假设，我们在RUNX/CBF β界面产生了一系列CBF β突变体，并测试了它们稳定Vif和影响RUNX依赖性启动子转录的能力。虽然几个CBF β氨基酸取代破坏了启动子活性，但这些都不影响CBF β稳定Vif或增强APOBEC 3G降解的能力。CBF β表面残基的诱变筛选鉴定出单个氨基酸变化F68 D，其破坏Vif结合及其降解APOBEC 3G的能力。该突变体仍然结合RUNX并刺激RUNX依赖性转录。这些功能分离突变体表明，HIV-1 Vif和RUNX转录因子在遗传上不同的表面上与细胞CBF β相互作用。
Human immunodeficiency virus type 1 (HIV-1) requires the cellular transcription factor core binding factor subunit beta (CBF beta) to stabilize its viral infectivity factor (Vif) protein and neutralize the APOBEC3 restriction factors. CBF beta normally heterodimerizes with the RUNX family of transcription factors, enhancing their stability and DNA-binding affinity. To test the hypothesis that Vif may act as a RUNX mimic to bind CBF beta, we generated a series of CBF beta mutants at the RUNX/CBF beta interface and tested their ability to stabilize Vif and impact transcription at a RUNX-dependent promoter. While several CBF beta amino acid substitutions disrupted promoter activity, none of these impacted the ability of CBF beta to stabilize Vif or enhance degradation of APOBEC3G. A mutagenesis screen of CBF beta surface residues identified a single amino acid change, F68D, that disrupted Vif binding and its ability to degrade APOBEC3G. This mutant still bound RUNX and stimulated RUNX-dependent transcription. These separation-of-function mutants demonstrate that HIV-1 Vif and the RUNX transcription factors interact with cellular CBF beta on genetically distinct surfaces.