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The TFE3 and MITF master transcription factors maintain metabolic homeostasis by regulating lysosomal, melanocytic, and autophagy genes. Previous studies posited that their cytosolic retention by 14-3-3, mediated by the Rag GTPases-mTORC1, was key for suppressing transcriptional activity in the presence of nutrients. Here, we demonstrate using mammalian cells that regulated protein stability plays a fundamental role in their control. Amino acids promote the recruitment of TFE3 and MITF to the lysosomal surface via the Rag GTPases, activating an evolutionarily conserved phospho-degron and leading to ubiquitination by CUL1 β-TrCP and degradation. Elucidation of the minimal functional degron revealed a conserved alpha-helix required for interaction with RagA, illuminating the molecular basis for a severe neurodevelopmental syndrome caused by missense mutations in TFE3 within the RagA-TFE3 interface. Additionally, the phospho-degron is recurrently lost in TFE3 genomic translocations that cause kidney cancer. Therefore, two divergent pathologies converge on the loss of protein stability regulation by nutrients., Competing Interests: Declaration of interests S.J.E. is a founder of TSCAN Therapeutics, MAZE Therapeutics, ImmuneID, and Mirimus and serves on the scientific advisory boards of Homology Medicines, ImmuneID, MAZE Therapeutics, TSCAN Therapeutics, and Molecular Cell; P.A.C. is a consultant at Scorpion Therapeutics. None of these affect this work., (Copyright © 2022 Elsevier Inc. All rights reserved.)