Autophagy facilitates IFN-δ-induced Jak2-STAT1 activation and cellular inflammation

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

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63 Citations (Scopus)

Abstract

Autophagy is regulated for IFN-γ-mediated antimicrobial efficacy; however, its molecular effects for IFN-γ signaling are largely unknown. Here, we show that autophagy facilitates IFN-γ-activated Jak2-STAT1. IFN-γ induces autophagy in wild-type but not in autophagy protein 5 (Atg5-/-)-deficient mouse embryonic fibroblasts (MEFs), and, autophagy-dependently, IFN-γ 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-γ receptor expression, resistant to IFN-γ-activated Jak2-STAT1, which suggests that autophagy is important for IFN-γ signal transduction. Lentivirus-based short hairpin RNA for Atg5 knockdown confirmed the importance of autophagy for IFN-γ-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-γ-induced activation of STAT1 in Atg5-/- MEFs. Our study provides evidence that there is a link between autophagy and both IFN-γ signaling and cellular inflammation and that autophagy, because it inhibits the expression of reactive oxygen species and SHP2, is pivotal for Jak2-STAT1 activation.

Original languageEnglish
Pages (from-to)28715-28722
Number of pages8
JournalJournal of Biological Chemistry
Volume285
Issue number37
DOIs
Publication statusPublished - 2010 Sep 10

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Chang, Y. P., Tsai, C. C., Huang, W. C., Wang, C. Y., Chen, C. L., Lin, Y. S., Kai, J. I., Hsieh, C. Y., Cheng, Y. L., Choi, P. C., Chen, S. H., Chang, S. P., Liu, H. S., & Lin, C. F. (2010). Autophagy facilitates IFN-δ-induced Jak2-STAT1 activation and cellular inflammation. Journal of Biological Chemistry, 285(37), 28715-28722. https://doi.org/10.1074/jbc.M110.133355