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The rabies virus matrix protein (RABV M) interacts with host histone deacetylase 6 (HDAC6) to activate the MEK/ ERK signaling pathway and enhance viral replication

文献类型： 外文期刊

作者： Juanbin Yin;Shasha Wang;Zhixiong Zhang;Junwei Ge;Qiang Zhang;Yuefeng Sun;Xiangping Yin;Xiangwei Wang

作者机构：

关键词： HDAC6;M protein;MEK/ERK pathway;RABV;Virus replication

期刊名称： Veterinary Microbiology

ISSN： 0378-1135

年卷期： 2025 年 305 卷

页码：

收录情况： SCIE（2025版）

摘要： Rabies virus (RABV) is the causative agent of rabies, posing a severe threat to human and animal health. The matrix (M) protein of RABV plays crucial roles during viral infection. In this study, we identified RABV M protein interacted with host histone deacetylase 6 (HDAC6) through a combination of immunoprecipitation and mass spectrometry analysis. Specifically, the catalytic domains of HDAC6 (amino acids 435–835) was shown to be critical for the interaction between HDAC6 and the RABV M protein. Overexpression of HDAC6 significantly enhanced RABV replication, whereas inhibition of HDAC6 expression or its deacetylase activity had the opposite effect，indicating that HDAC6 is a positive regulator of RABV replication. We further determined that RABV infection actives the MEK/ERK pathway, and inhibition of this pathway with U0126 significantly reduced viral titers. Moreover, HDAC6 positively regulated MEK/ERK pathway activation in a manner independent of its deacetylase activity but dependent on the presence of HDAC6 during virus infection. Finally, we demonstrated that co-expression of RABV M enhanced the role of HDAC6 in facilitating MEK/ERK pathway activation. Collectively, our findings demonstrate that RABV exploits the HDAC6-M interaction to hijack the MEK/ERK signaling axis, which is essential for viral replication. Notably, HDAC6 facilitates MEK/ERK activation in a deacetylase activity-independent manner, revealing a novel mechanism by which viruses manipulate host machinery. These results highlight HDAC6 as a potential therapeutic target for combating rabies.

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