Autophagy Facilitates IFN-gamma-induced Jak2-STAT1 Activation and Cellular Inflammation

作者：Chang Yu Ping; Tsai Cheng Chieh; Huang Wei Ching; Wang Chi Yun; Chen Chia Ling; Lin Yee Shin; Kai Jui In; Hsieh Chia Yuan; Cheng Yi Lin; Choi Pui Ching; Chen Shun Hua; Chang Shih Ping; Liu Hsiao Sheng; Lin Chiou Feng^*

来源：JOURNAL OF BIOLOGICAL CHEMISTRY, 2010, 285(37): 28715-28722.

DOI：10.1074/jbc.M110.133355

Autophagy is regulated for IFN-gamma-mediated antimicrobial efficacy; however, its molecular effects for IFN-gamma signaling are largely unknown. Here, we show that autophagy facilitates IFN-gamma-activated Jak2-STAT1. IFN-gamma induces autophagy in wild-type but not in autophagy protein 5 (Atg5(-/-))-deficient mouse embryonic fibroblasts (MEFs), and, autophagy-dependently, IFN-gamma induces IFN regulatory factor 1 and cellular inflammatory responses. Pharmacologically inhibiting autophagy using 3-methyladenine, a known inhibitor of class III phosphatidylinositol 3-kinase, confirms these effects. Either Atg5(-/-) or Atg7(-/-) MEFs are, independent of changes in IFN-gamma receptor expression, resistant to IFN-gamma-activated Jak2-STAT1, which suggests that autophagy is important for IFN-gamma signal transduction. Lentivirus-based short hairpin RNA for Atg5 knockdown confirmed the importance of autophagy for IFN-gamma-activated STAT1. Without autophagy, reactive oxygen species increase and cause SHP2 (Src homology-2 domain-containing phosphatase 2)-regulated STAT1 inactivation. Inhibiting SHP2 reversed both cellular inflammation and the IFN-gamma-induced activation of STAT1 in Atg5(-/-) MEFs. Our study provides evidence that there is a link between autophagy and both IFN-gamma signaling and cellular inflammation and that autophagy, because it inhibits the expression of reactive oxygen species and SHP2, is pivotal for Jak2-STAT1 activation.

• 出版日期2010-9-10