<br>氨基酸传感器 GCN2 通过抑制炎症小体激活来控制肠道炎症,Nature

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氨基酸传感器 GCN2 通过抑制炎症小体激活来控制肠道炎症
Nature ( IF 50.5 ) Pub Date : 2016-03-01 , DOI: 10.1038/nature17186
Rajesh Ravindran ₁ , Jens Loebbermann ₁ , Helder I Nakaya ₂ , Nooruddin Khan ₃ , Hualing Ma ₁ , Leonardo Gama ₂ , Deepa K Machiah ₄ , Benton Lawson ₅ , Paul Hakimpour ₁ , Yi-Chong Wang ₁ , Shuzhao Li ₁ , Prachi Sharma ₄ , Randal J Kaufman ₆ , Jennifer Martinez ₇ , Bali Pulendran ₁

Affiliation

综合应激反应（ISR）是一种稳态机制，真核细胞通过该机制感知并响应应激诱导信号，例如氨基酸饥饿。通用控制非抑制 (GCN2) 激酶是 ISR 的关键协调器，并调节蛋白质合成以应对氨基酸饥饿。在这里，我们在小鼠中证明 GCN2 通过抑制炎症小体激活来控制肠道炎症。在氨基酸饥饿或肠道炎症期间，肠道抗原呈递细胞 (APC) 和上皮细胞中 ISR 的激活增强。 CD11c+ APC 或肠上皮细胞中 Gcn2（也称为 Eif2ka4）的基因缺失导致炎症体激活和白细胞介素 (IL)-1β 产生增强，从而导致肠道炎症和辅助 T 17 细胞 (TH17) 反应增强。这是由于 Gcn2−/− 肠道 APC 和上皮细胞自噬减少导致活性氧 (ROS) 增加，而活性氧是炎症小体的有效激活剂。因此，肠道 APC 中 Atg5 或 Atg7 的条件性消融导致 ROS 和 TH17 反应增强。此外，体内 ROS 和 IL-1β 的阻断可抑制 Gcn2−/− 小鼠的 TH17 反应并减少炎症。重要的是，急性氨基酸饥饿通过依赖 GCN2 的机制抑制肠道炎症。这些结果揭示了一种将氨基酸传感与通过 GCN2 控制肠道炎症相结合的机制。

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The amino acid sensor GCN2 controls gut inflammation by inhibiting inflammasome activation

The integrated stress response (ISR) is a homeostatic mechanism by which eukaryotic cells sense and respond to stress-inducing signals, such as amino acid starvation. General controlled non-repressed (GCN2) kinase is a key orchestrator of the ISR, and modulates protein synthesis in response to amino acid starvation. Here we demonstrate in mice that GCN2 controls intestinal inflammation by suppressing inflammasome activation. Enhanced activation of ISR was observed in intestinal antigen presenting cells (APCs) and epithelial cells during amino acid starvation, or intestinal inflammation. Genetic deletion of Gcn2 (also known as Eif2ka4) in CD11c+ APCs or intestinal epithelial cells resulted in enhanced intestinal inflammation and T helper 17 cell (TH17) responses, owing to enhanced inflammasome activation and interleukin (IL)-1β production. This was caused by reduced autophagy in Gcn2−/− intestinal APCs and epithelial cells, leading to increased reactive oxygen species (ROS), a potent activator of inflammasomes. Thus, conditional ablation of Atg5 or Atg7 in intestinal APCs resulted in enhanced ROS and TH17 responses. Furthermore, in vivo blockade of ROS and IL-1β resulted in inhibition of TH17 responses and reduced inflammation in Gcn2−/− mice. Importantly, acute amino acid starvation suppressed intestinal inflammation via a mechanism dependent on GCN2. These results reveal a mechanism that couples amino acid sensing with control of intestinal inflammation via GCN2.

更新日期：2016-03-01

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