title: Autophagy facilitates IFN-gamma-induced Jak2-STAT1 activation and cellular inflammation.
abstract: 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.
authors.affiliation: Institutes of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.
authors.forename: Yu-Ping
authors.initials: YP
authors.lastname: Chang
authors.forename: Cheng-Chieh
authors.initials: CC
authors.lastname: Tsai
authors.forename: Wei-Ching
authors.initials: WC
authors.lastname: Huang
authors.forename: Chi-Yun
authors.initials: CY
authors.lastname: Wang
authors.forename: Chia-Ling
authors.initials: CL
authors.lastname: Chen
authors.forename: Yee-Shin
authors.initials: YS
authors.lastname: Lin
authors.forename: Jui-In
authors.initials: JI
authors.lastname: Kai
authors.forename: Chia-Yuan
authors.initials: CY
authors.lastname: Hsieh
authors.forename: Yi-Lin
authors.initials: YL
authors.lastname: Cheng
authors.forename: Pui-Ching
authors.initials: PC
authors.lastname: Choi
authors.forename: Shun-Hua
authors.initials: SH
authors.lastname: Chen
authors.forename: Shih-Ping
authors.initials: SP
authors.lastname: Chang
authors.forename: Hsiao-Sheng
authors.initials: HS
authors.lastname: Liu
authors.forename: Chiou-Feng
authors.initials: CF
authors.lastname: Lin
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001343:Autophagy / Q000502:physiology*; D000071187:Autophagy-Related Protein 5; D000071193:Autophagy-Related Protein 7; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism*; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism*; D016086:Lentivirus; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D000225:Adenine; D000071187:Autophagy-Related Protein 5; D000071193:Autophagy-Related Protein 7; D004791:Enzyme Inhibitors; D007371:Interferon-gamma; D053614:Janus Kinase 2; D008869:Microtubule-Associated Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017382:Reactive Oxygen Species; D050794:STAT1 Transcription Factor; C495773:Atg5 protein, mouse; C502661:Atg7 protein, mouse; C494080:Stat1 protein, mouse; C025946:3-methyladenine; C507926:Jak2 protein, mouse; C516725:Ptpn11 protein, mouse