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

Abstract

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.

Interferon‐γ‐induced insufficient autophagy contributes to p62‐dependent apoptosis of epithelial cells in chronic rhinosinusitis with nasal polyps

“…p38 mitogen‐activated protein kinases, interferon‐regulatory factor‐1, mammalian target of rapamycin complex 1, and activating transcription factor 6 have been implicated in IFN‐γ‐induced autophagy in different cell types . Indoleamine 2,3‐dioxygenase‐mediated tryptophan depletion has been indicated in IFN‐γ‐induced autophagy in human kidney epithelial cells . We did find that the expression of indoleamine 2,3‐dioxygenase and the production of tryptophan metabolite (kynurenine) were increased in both eosinophilic and noneosinophilic polyps compared with controls (data not shown).…”

14-3-3 Proteins regulate Akt Thr308 phosphorylation in intestinal epithelial cells

“…28,29 This led us to speculate that autophagymediated degradation of 14-3-3η was occurring during inflammation. We investigated the presence of autophagy in the mucosa of colitic mice by analyzing the conversion of the autophagosomal marker LC3-I to LC3-II 31,32 and the presence of ATG5, a protein that is essential for autophagosome formation.…”

Therapeutic targeting of inflammation and tryptophan metabolism in colon and gastrointestinal cancer

“…Mechanistic studies eventually determined that local tryptophan depletion is itself immunosuppressive, but that these effects are also mediated by several KP metabolites 30, 40 . Low levels of tryptophan in the local microenvironment activate stress-response pathways, including GCN2 kinase and mTOR 41, 42 . Some KP metabolites bind the aryl hydrocarbon receptor (AHR) to promote forkhead box (FOX) P3 + regulatory T cell (Tregs) differentiation 43–46 .…”