IDO inhibits a tryptophan sufficiency signal that stimulates mTOR: A novel IDO effector pathway targeted by D-1-methyl-tryptophan.

ABSTRACT: Tryptophan catabolism by indoleamine 2,3-dioxygenase (IDO) alters inflammation and favors T-cell tolerance in cancer, but the underlying molecular mechanisms remain poorly understood. The integrated stress response kinase GCN2, a sensor of uncharged tRNA that is activated by amino acid deprivation, is recognized as an important effector of the IDO pathway. However, in a mouse model of inflammatory carcinogenesis, ablation of Gcn2 did not promote resistance against tumor development like the absence of IDO does, implying the existence of additional cancer-relevant pathways that operate downstream of IDO. Addressing this gap in knowledge, we report that the IDO-mediated catabolism of tryptophan also inhibits the immunoregulatory kinases mTOR and PKC-Θ, along with the induction of autophagy.

SUBMITTER: Metz R 

PROVIDER: S-EPMC3525601 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature