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

Research output: Contribution to journalArticle

62 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 - Sep 10 2010

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Autophagy
Fibroblasts
Chemical activation
Inflammation
Class III Phosphatidylinositol 3-Kinases
Reactive Oxygen Species
SH2 Domain-Containing Protein Tyrosine Phosphatases
Signal transduction
Small Interfering RNA
Proteins
Lentivirus
Signal Transduction

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Medicine(all)

Cite this

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

In: Journal of Biological Chemistry, Vol. 285, No. 37, 10.09.2010, p. 28715-28722.

Research output: Contribution to journalArticle

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, CF 2010, 'Autophagy facilitates IFN-δ-induced Jak2-STAT1 activation and cellular inflammation', Journal of Biological Chemistry, vol. 285, no. 37, pp. 28715-28722. https://doi.org/10.1074/jbc.M110.133355
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. / Autophagy facilitates IFN-δ-induced Jak2-STAT1 activation and cellular inflammation. In: Journal of Biological Chemistry. 2010 ; Vol. 285, No. 37. pp. 28715-28722.
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