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J. Biol. Chem. 285 (37): 28715-28722

© 2010 by The American Society for Biochemistry and Molecular Biology, Inc.

Autophagy Facilitates IFN-{gamma}-induced Jak2-STAT1 Activation and Cellular Inflammation*Formula

Yu-Ping Chang{ddagger}§, Cheng-Chieh Tsai{ddagger}||, Wei-Ching Huang{ddagger}, Chi-Yun Wang{ddagger}, Chia-Ling Chen§, Yee-Shin Lin§**, Jui-In Kai{ddagger}, Chia-Yuan Hsieh{ddagger}, Yi-Lin Cheng{ddagger}{ddagger}{ddagger}, Pui-Ching Choi{ddagger}, Shun-Hua Chen§, Shih-Ping Chang§, Hsiao-Sheng Liu§, , and Chiou-Feng Lin{ddagger}§1

From the Institutes of {ddagger}Clinical Medicine and
Basic Medical Sciences,
Departments of §Microbiology and Immunology and
{ddagger}{ddagger}Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan,
the ||Department of Nursing, Chung Hwa University of Medical Technology, Tainan 717, Taiwan, and
the **Center for Gene Regulation and Signal Transduction Research, National Cheng Kung University, Tainan 701, Taiwan

ABSTRACT Back to Top

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.


Key Words: Autophagy • Inflammation • Interferon • Jak Kinase • Phosphatase • Reactive Oxygen Species (ROS) • Signal Transduction • STAT Transcription Factor

Received for publication April 13, 2010. Revision received June 21, 2010.

1 To whom correspondence should be addressed: Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan. Tel.: 886-6-235-3535 (ext. 4240); Fax: 886-6-275-8781; E-mail: cflin{at}mail.ncku.edu.tw.


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