肌球蛋白1F（MYO1F）将环鸟苷酸-腺苷酸合成酶（cGAS）定位在质膜上，以确保完整且功能性的信号传导。
MYO1F positions cGAS on the plasma membrane to ensure full and functional signaling.
作者信息
Wang Heping, Cui Zhihui, Sun Wanwei, Yi Ming, Cheng Yuheng, Zhang Yunpeng, Du Yanyun, Pan Ting, Gao Ru, Feng Lingyun, Zeng Bo, Huang Guoling, Li Yangyang, Wang Yuan, Zhang Cun-Jin, He Ruirui, Wang Chenhui
机构信息
Key Laboratory of Molecular Biophysics of the Ministry of Education, National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, 430074 Wuhan, China; The Key Laboratory for Human Disease Gene Study of Sichuan Province and the Department of Laboratory Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, 611731 Chengdu, China.
The Key Laboratory for Human Disease Gene Study of Sichuan Province and the Department of Laboratory Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, 611731 Chengdu, China; Sichuan Medical Laboratory Clinical Medical Research Center, Sichuan Provincial People's Hospital, 611731 Chengdu, China; Research Unit for Blindness Prevention of the Chinese Academy of Medical Sciences, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, Sichuan, China; School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610054, China.
出版信息
Mol Cell. 2025 Jan 2;85(1):150-165.e7. doi: 10.1016/j.molcel.2024.11.026. Epub 2024 Dec 17.
Cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase (cGAS) detects viral or endogenous DNA, activating the innate immune response to infections and autoimmune diseases. Upon binding to double-stranded DNA, cGAS synthesizes 2'3' cGMP-AMP, which triggers type I interferon production. Besides its presence in the cytosol and nucleus, cGAS is found at the plasma membrane, although its significance remains unclear. Here, we report that cGAS associates with myosin 1F (MYO1F) at the plasma membrane of human and mouse macrophages. During viral infection, phosphorylation of MYO1F by spleen-associated tyrosine kinase (SYK) facilitates the recruitment of lysine acetyltransferase 2A (KAT2A), which acetylates cGAS at lysine residues 421, 292, and 131, essential for its activation. Moreover, membrane-localized cGAS is crucial for signaling activation and type I interferon production triggered by virus-cell fusion due to Mn release from organelles. Our results highlight the importance of MYO1F-mediated cGAS localization for its full activation in response to viral infection.
环磷酸鸟苷（GMP）-环磷酸腺苷（AMP）合酶（cGAS）可检测病毒或内源性DNA，激活针对感染和自身免疫性疾病的先天免疫反应。与双链DNA结合后，cGAS会合成2'3' cGMP-AMP，从而触发I型干扰素的产生。除了存在于细胞质和细胞核中，cGAS还存在于质膜上，但其意义尚不清楚。在此，我们报告cGAS在人和小鼠巨噬细胞的质膜上与肌球蛋白1F（MYO1F）相关联。在病毒感染期间，脾相关酪氨酸激酶（SYK）对MYO1F的磷酸化促进了赖氨酸乙酰转移酶2A（KAT2A）的募集，KAT2A会使cGAS的赖氨酸残基421、292和131乙酰化，这些残基对其激活至关重要。此外，膜定位的cGAS对于由细胞器释放的锰导致的病毒-细胞融合引发的信号激活和I型干扰素产生至关重要。我们的结果突出了MYO1F介导的cGAS定位对其在病毒感染时完全激活的重要性。
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