美国华盛顿大学Daniel B. Stetson课题组发现，蛋白激酶R和综合应激反应驱动RNA脱氨酶ADAR1突变引起的免疫病理学。2021年8月2日，《免疫》杂志在线发表了这项成果。

研究人员表示，RNA脱氨酶ADAR1是RNA传感器MDA5的一个重要的负向调节因子，ADAR1功能的丧失会引发MDA5被自身RNA不适当地激活。编码ADAR1的基因ADAR的突变导致人类免疫疾病，包括Aicardi-Goutières综合症（AGS）。然而，MDA5依赖的疾病在体内的发病机制仍然是未知的。

研究人员获得了在ADAR1中具有单个氨基酸变化的小鼠，模拟了人类最常见的ADAR AGS突变。这些Adar突变体小鼠患上了需要MDA5、RIG-I样受体LGP2、I型干扰素和eIF2α激酶PKR的致死性疾病。一种作用于eIF2α磷酸化下游的综合应激反应（ISR）的小分子抑制剂可以防止免疫病理学并将小鼠从死亡中解救出来。这些发现使PKR和ISR成为体内免疫病理学的核心组成部分，并确定了治疗与ADAR1-MDA5轴相关人类疾病的靶标。

附：英文原文

Title: Protein kinase R and the integrated stress response drive immunopathology caused by mutations in the RNA deaminase ADAR1

Author: Megan Maurano, Jessica M. Snyder, Caitlin Connelly, Jorge Henao-Mejia, Carmela Sidrauski, Daniel B. Stetson

Issue&Volume: 2021-08-02

Abstract: The RNA deaminase ADAR1 is an essential negative regulator of the RNA sensor MDA5,and loss of ADAR1 function triggers inappropriate activation of MDA5 by self-RNAs.Mutations in ADAR, the gene that encodes ADAR1, cause human immune diseases, including Aicardi-Goutièressyndrome (AGS). However, the mechanisms of MDA5-dependent disease pathogenesis in vivo remain unknown. Here we generated mice with a single amino acid change in ADAR1 thatmodels the most common human ADAR AGS mutation. These Adar mutant mice developed lethal disease that required MDA5, the RIG-I-like receptorLGP2, type I interferons, and the eIF2α kinase PKR. A small-molecule inhibitor ofthe integrated stress response (ISR) that acts downstream of eIF2α phosphorylationprevented immunopathology and rescued the mice from mortality. These findings placePKR and the ISR as central components of immunopathology in vivo and identify therapeutic targets for treatment of human diseases associated withthe ADAR1-MDA5 axis.

DOI: 10.1016/j.immuni.2021.07.001

Source: https://www.cell.com/immunity/fulltext/S1074-7613(21)00263-6