Phosphoinositide Interactions Position cGAS at the Plasma Membrane to Ensure Efficient Distinction between Self- and Viral DNA
Phosphoinositide Interactions Position cGAS at the Plasma Membrane to Ensure Efficient Distinction between Self- and Viral DNA
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DOI：
10.1016/j.cell.2019.01.049
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发表时间：
2019-03-07
期刊：
影响因子：
64.5
通讯作者：
Kagan, Jonathan C.
中科院分区：
文献类型：
--
作者：
Barnett, Katherine C.;Coronas-Serna, Julia M.;Kagan, Jonathan C.
哺乳动物细胞胞浆中DNA的存在是一种不寻常的事件，通常与遗传毒性应激或病毒感染有关。CGAS酶是胞浆DNA的传感器，可以诱导干扰素和炎症反应，根据环境的不同，这些反应可以是保护性的，也可以是病理的。与其他胞质天然免疫受体一样，cGAS被认为散布在胞浆中，寻找其DNA配体。在此，我们报道了cGAS不是胞浆蛋白，而是通过N-末端磷脂酰肌醇结合域的作用定位于质膜。该结构域选择性地与PI(4，5)P-2相互作用，脂质结合缺陷的cGAS突变体错误地定位于胞浆和核室。错误定位的cGAS可诱导干扰素对基因毒性应激的强烈反应，但对病毒感染的反应较弱。这些数据确立了胞浆天然免疫受体的亚细胞定位，这是一种管理自我非自我歧视的机制。
The presence of DNA in the cytosol of mammalian cells is an unusual event that is often associated with genotoxic stress or viral infection. The enzyme cGAS is a sensor of cytosolic DNA that induces interferon and inflammatory responses that can be protective or pathologic, depending on the context. Along with other cytosolic innate immune receptors, cGAS is thought to diffuse throughout the cytosol in search of its DNA ligand. Herein, we report that cGAS is not a cytosolic protein but rather localizes to the plasma membrane via the actions of an N-terminal phosphoinositide-binding domain. This domain interacts selectively with PI(4,5)P-2, and cGAS mutants defective for lipid binding are mislocalized to the cytosolic and nuclear compartments. Mislocalized cGAS induces potent interferon responses to geno-toxic stress, but weaker responses to viral infection. These data establish the subcellular positioning of a cytosolic innate immune receptor as a mechanism that governs self-nonself discrimination.