Division of Gastroenterology, Boston Children's Hospital and Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
Division of Gastroenterology, Boston Children's Hospital and Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA; Departamento de Microbiología y Parasitología, Facultad de Farmacia. Universidad Complutense de Madrid e Instituto Ramón y Cajal de Investigaciones Sanitarias (IRYCIS), Plaza de Ramón y Cajal sn, 28040 Madrid, Spain.
Cell. 2019 Mar 7;176(6):1432-1446.e11. doi: 10.1016/j.cell.2019.01.049. Epub 2019 Feb 28.
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, and cGAS mutants defective for lipid binding are mislocalized to the cytosolic and nuclear compartments. Mislocalized cGAS induces potent interferon responses to genotoxic 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.
细胞质中哺乳动物细胞 DNA 的存在是一种异常事件，通常与遗传毒性应激或病毒感染有关。cGAS 酶是细胞质 DNA 的传感器，可诱导干扰素和炎症反应，其保护性或病理性取决于具体情况。与其他细胞质先天免疫受体一样，cGAS 被认为在细胞质中扩散以寻找其 DNA 配体。在此，我们报告 cGAS 不是细胞质蛋白，而是通过其 N 端磷酸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 相互作用，并且脂质结合缺陷的 cGAS 突变体错误定位到细胞质和核区室。定位错误的 cGAS 诱导强烈的干扰素反应来应对遗传毒性应激，但对病毒感染的反应较弱。这些数据确立了细胞质先天免疫受体的亚细胞定位作为区分自身和非自身的机制。
