Tryptophan depletion and the kinase GCN2 mediate IFN-γ-induced autophagy.
IFN-γ 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-γ are complex, and emerging evidence suggests that IFN-γ 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-γ activates autophagy in human kidney epithelial cells and provide new insights into how autophagy regulates immune functions in response to IFN-γ. Our results indicate that IFN-γ promotes tryptophan depletion, activates the eIF2α 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-γ-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-γ. These findings assign to IFN-γ a novel function in the regulation of autophagy, which, in turn, modulates IFN-γ-induced secretion of inflammatory cytokines.
INSERM U775, Paris, France.
Sophie
S
Fougeray
Iadh
I
Mami
Gildas
G
Bertho
Philippe
P
Beaune
Eric
E
Thervet
Nicolas
N
Pallet
D001343:Autophagy / Q000235:genetics / Q000276:immunology*; D002292:Carcinoma, Renal Cell / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000378:metabolism; D004847:Epithelial Cells / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism; D007371:Interferon-gamma / Q000502:physiology*; D007680:Kidney Neoplasms / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D014364:Tryptophan / Q000172:deficiency* / Q000378:metabolism / Q000502:physiology; D014407:Tumor Cells, Cultured
D016207:Cytokines; D018836:Inflammation Mediators; D007371:Interferon-gamma; D014364:Tryptophan; C529271:EIF2AK4 protein, human; D017346:Protein Serine-Threonine Kinases