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Histone deacetylase 6 inhibits STING-dependent antiviral immunity via site-specific deacetylation

文献类型： 外文期刊

作者： Min Qu;Dali Wei;Qunhua Ke;Pengyuan Cheng;Yiyuan Ma;Berihun Afera;Ke Guo;Miaomiao Li;Xiangping Yin;Xiangwei Wang;Jianlin Han;Yuefeng Sun

作者机构：

关键词： deacetylation;HDAC6;innate immunity;interferon;STING;VSV

期刊名称： Journal of Biological Chemistry

ISSN： 0021-9258

年卷期： 2025 年 301 卷 12 期

页码：

收录情况： SCIE（2025版） ; ; EI（2025版）

摘要： Histone deacetylase HDAC6 is a critical regulator of antiviral innate immunity, but its precise molecular mechanisms during RNA viral infection remain incompletely understood. In this study, we demonstrate that HDAC6 depletion (via siRNA knockdown or pharmacological inhibition) significantly suppresses vesicular stomatitis virus (VSV) replication. Further analysis revealed that HDAC6 modulates innate immune signaling by targeting the stimulator of interferon genes (STING) pathway, thereby attenuating type I interferon (IFN) responses. Mechanistically, HDAC6 directly interacts with STING and catalyzes its deacetylation at lysine 338 (K338). This post-translational modification impedes TBK1 recruitment by altering STING acetylation status, ultimately impairing STING phosphorylation at serine 366 (S366). Functional validation showed that overexpression of a STING with K338Q acetylation-mimetic mutant confers cellular resistance to VSV infection, establishing HDAC6-mediated STING deacetylation as a pivotal regulatory checkpoint in the antiviral response.

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