Immunology Autophagy for Inflammation

Nancy R. Gough

Science Signaling, AAAS, Washington, DC 20005, USA

Autophagy not only supplies nutrients through cellular digestion during periods of starvation but also contributes to the cellular response to infection. Chang et al. show that when autophagy is compromised, the cellular response to the proinflammatory cytokine interferon- (IFN-) is also compromised. Analysis of mouse embryo fibroblasts (MEFs) deficient in either Atg5 or Atg7, two proteins essential for the formation of autophagosomes, showed that various IFN-–mediated responses (reporter gene expression, nitrite generation, and cytokine production) were reduced compared with the responses of wild-type cells. Detailed examination of the signaling pathway in the Atg5-deficient cells revealed that the interaction between the IFN receptor and the kinase Jak2 was not affected but that Jak2 phosphorylation and phosphorylation of its downstream targets, such as Jak1, Pyk2, and STAT1, as well as expression of STAT1-dependent genes, were reduced. Atg5-deficient MEFs had greater amounts of mitochondria and were in a more oxidative state relative to wild-type MEFs. Consistent with a role for reactive oxygen species (ROS) in mediating the differences in IFN- responsiveness between autophagy-competent and autophagy-impaired cells, treatment of wild-type MEFS with an antioxidant increased IFN-–mediated STAT1 phosphorylation, and the addition of hydrogen peroxide inhibited this response. The phosphatase SHP2 is activated by ROS, and knockdown of SHP2 in the Atg5-deficient MEFs restored IFN-–mediated STAT1 phosphorylation. Thus, the authors propose that autophagy limits mitochondrially produced ROS, which limits phosphatase activity, allowing IFN- signaling to proceed.

Y.-P. Chang, C.-C. Tsai, W.-C. Huang, C.-Y. Wang, C.-L. Chen, Y.-S. Lin, J.-I. Kai, C.-Y. Hsieh, Y.-L. Cheng, P.-C. Choi, S.-H. Chen, S.-P. Chang, H.-S. Liu, C.-F. Lin, Autophagy facilitates IFN--induced Jak2-STAT1 activation and cellular inflammation. J. Biol. Chem. 285, 28715–28722 (2010). [Abstract] [Full Text]

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