HDAC6调控病毒在细胞内降解的分子机制

Antibody-dependent intracellular neutralization (ADIN) resist viral pathogen infection as the last line of defense. The tripartite motif protein 21 (TRIM21) has been identified as a cytosolic antibody receptor, which plays critical role in ADIN. TRIM21 acts as the intracellular antibody Fc receptor to target the internalized virus-antibody complexes to the proteasome for degradation before virus has time to replicate. The regulation of TRIM21 function by post-translational modifications (PTMs) needs to be further illustrated, except for ubiquitination. In our previous study of the substrate diversity of histone deacetylase 6 (HDAC6), we found that TRIM21 was included in the list of acetylated proteins. In this study, we will dissect deeply the molecular mechanism of how HDAC6 catalyze the deacetylation of TRIM21, also will explain the functional effects regulated by TRIM21 deacetylation, further will perfect ADIN signaling pathway mediated by TRIM21. If we finally achieve the end of our research, it is expected to know more about the mechanism of ADIN mediated by TRIM21, which has important theoretical and academic value.

抗体依赖的细胞内中和效应作为机体最后一道防线，抵抗病毒感染。The tripartite motif protein 21 (TRIM21)作为胞浆内Fc受体，在其中起着关键作用。TRIM21可以识别胞浆内病毒-抗体复合物并将其靶定到蛋白酶体进行降解，致使病毒不能在细胞内发生复制。除泛素化修饰外，蛋白其他翻译后修饰如何调控TRIM21功能有待拓展和深入。前期研究发现，TRIM21作为乙酰化修饰蛋白出现在HDAC6底物多样性列表中。在该项目中，我们将深度分析HDAC6催化TRIM21发生去乙酰化修饰的分子作用机制，深度阐释TRIM21去乙酰化修饰对其功能的影响，进一步完善TRIM21介导的细胞内抗体依赖的中和效应的信号通路。预期研究结果的取得，将加深对TRIM21介导抗体依赖的细胞内中和效应作用机制的理解，提高对抗体依赖的细胞内中和效应作用机制认知，具有重要的理论和学术价值。

The tripartite motif protein 21 (TRIM21)可以识别胞浆内病毒-抗体复合物并将其靶定到蛋白酶体进行降解，致使病毒不能在细胞内发生复制。但是调控TRIM21活性的分子机制还不清楚。我们研究发现，HDAC6可以调控TRIM21发生去乙酰化，而且TRIM21通过PRYSPRY 结构域与HDAC6发生相互作用。进一步研究发现，HDAC6催化TRIM21在其385位赖氨酸和387位赖氨酸发生去乙酰化，进而引发TRIM21发生同源二聚化。抑制HDAC6活性会使TRIM21乙酰化水平增加，而TRIM21高度乙酰化会抑制TRIM21发生同源二聚化和泛素化修饰，进而抑制其结合病毒抗体复合物的能力，从而减少病毒抗体复合物通过泛素蛋白媒体通路降解，进而抑制了细胞内抗体依赖的中和效应，最终导致病毒在细胞内累积。而TRIM21乙酰化缺失的突变体K385/387R，会恢复由HDAC6缺失引发的抗体依赖的细胞内中和效应能力。该项目证明了HDAC6可以调控TRIM21介导的细胞内固有免疫反应。