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 Mn²⁺ release from organelles. Our results highlight the importance of MYO1F-mediated cGAS localization for its full activation in response to viral infection.

中文翻译：

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MYO1F 将 cGAS 定位在质膜上，以确保信号转导完整且功能齐全


环磷酸鸟苷 （GMP）-单磷酸腺苷 （AMP） 合酶 （cGAS） 检测病毒或内源性 DNA，激活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 合成 2′3′ cGMP-AMP，从而触发 I 型干扰素的产生。除了存在于胞质溶胶和细胞核中外，cGAS 还存在于质膜上，但其意义尚不清楚。在这里，我们报道了 cGAS 与人和小鼠巨噬细胞质膜上的肌球蛋白 1F （MYO1F） 相关。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 乙酰化赖氨酸残基 421、292 和 131 位点的 cGAS，这是其激活所必需的。此外，由于细胞器释放 Mn²⁺，膜定位的 cGAS 对于病毒-细胞融合触发的信号激活和 I 型干扰素产生至关重要。我们的结果强调了 MYO1F 介导的 cGAS 定位对于其响应病毒感染而完全激活的重要性。