Tryptophan Depletion and the Kinase GCN2 Mediate IFN-γ-Induced Autophagy

IFN-gamma is a master regulator of the immune responses that occur in the transplanted kidney, acting both on the immune system and on the graft itself. The cellular responses to IFN-gamma are complex, and emerging evidence suggests that IFN-gamma may regulate autophagic functions. Conversely, autophagy modulates innate and adaptive immune functions in various contexts. In this study, we identify a novel mechanism by which IFN-gamma activates autophagy in human kidney epithelial cells and provide new insights into how autophagy regulates immune functions in response to IFN-gamma. Our results indicate that IFN-gamma promotes tryptophan depletion, activates the eIF2 alpha kinase general control nonderepressible-2 (GCN2), and leads to an increase in the autophagic flux. Further, tryptophan supplementation and RNA interference directed against GCN2 inhibited IFN-gamma-induced autophagy. This process is of functional relevance because autophagy regulates the secretion of inflammatory cytokines and growth factors by human kidney epithelial cells in response to IFN-gamma. These findings assign to IFN-gamma a novel function in the regulation of autophagy, which, in turn, modulates IFN-gamma-induced secretion of inflammatory cytokines. The Journal of Immunology, 2012, 189: 2954-2964.