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Free keywords:
RENAL-CELL CARCINOMA; TRANSCRIPTION FACTOR; GENE FUSION; RAG GTPASES;
TRANSLOCATION; IDENTIFICATION; MICROPHTHALMIA; DEFINES; GROWTH;
UBIQUITINATIONBiochemistry & Molecular Biology; Cell Biology;
Abstract:
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, medi-ated by the Rag GTPases-mTORC1, was key for suppressing transcriptional activity in the presence of nu-trients. 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 CUL1b-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 syn-drome caused by missense mutations in TFE3 within the RagA-TFE3 interface. Additionally, the phospho-de-gron 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.
