The MTORC1-AHR pathway sustains translation and autophagy in tumours under tryptophan stress

Tumours face tryptophan (Trp) depletion, but the mechanisms sustaining protein biosynthesis under Trp stress remain unclear. We report that Trp stress increases the levels of the translation repressor EIF4EBP1. Yet, at the same time, EIF4EBP1 is selectively phosphorylated by the metabolic master regulator MTORC1 kinase, preventing EIF4EBP1 from inhibiting translation. MTORC1 activity under Trp stress is unexpected because the absence of amino acids is typically linked with MTORC1 inhibition. EIF4EBP1-sensitive translation in Trp starved cells is sustained by EGFR and RAS signalling to MTORC1. Via this mechanism, Trp stress enhances the synthesis and activity of the aryl hydrocarbon receptor (AHR). This is noteworthy as Trp catabolites are known to activate AHR, and therefore Trp stress was previously considered to inhibit AHR. Trp stress-induced AHR enhances the expression of key regulators of autophagy, which sustains intracellular Trp levels and Trp-charged tRNAs for translation. Hence, Trp stress switches MTORC1 from its established inhibitory function into an enhancer of autophagy, acting through AHR. The clinical potential of this fundamental mechanism is highlighted by the activity of the mTORC1-AHR pathway and an autophagy signature in 20% of glioblastoma patients, opening up new avenues for cancer therapy. ### Competing Interest Statement AS, ST and CO are founders and AS and CO are managing directors of cAHRmeleon Bioscience GmbH. VIK is a Scientific Advisor for Longaevus Technologies. Authors of this manuscript have patents on AHR inhibitors in cancer (WO2013034685, CO); A method to multiplex tryptophan and its metabolites (WO2017072368, CO); A transcriptional signature to determine AHR activity (WO2020201825, AS, ST, CO); Interleukin-4-induced gene 1 (IL4I1) as a biomarker (WO2020208190, AS, ST, LFSP, MTP, CO) Interleukin-4-induced gene 1 (IL4I1) and its metabolites as biomarkers for cancer (WO2021116357, AS, ST, LFSP, CO); a targeted proteomics method to monitor autophagy (EP23182541, AL, JD).