{"doi":"10.1016/j.molcel.2022.12.013","title":"A central role for regulated protein stability in the control of TFE3 and MITF by nutrients","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, 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 CUL1β−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.","journal":"Molecular Cell","year":2023,"id":320169,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":50,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9474,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":816276,"name":"Brad A. Palanski","orcid":"0000-0002-4049-4274","position":1,"is_corresponding":false},{"id":258414,"name":"Daniel C. Scott","orcid":"0000-0002-7688-5568","position":2,"is_corresponding":false},{"id":108413,"name":"Richard T. Timms","orcid":"0000-0001-7275-597X","position":3,"is_corresponding":false},{"id":1030627,"name":"Karl W. Barber","orcid":"0000-0003-0672-8409","position":4,"is_corresponding":false},{"id":860482,"name":"Xin Gu","orcid":"0009-0009-3207-012X","position":5,"is_corresponding":false},{"id":1016940,"name":"Aoyue Mao","orcid":"0000-0001-5690-8120","position":6,"is_corresponding":false},{"id":108415,"name":"Yumei Leng","orcid":"0000-0003-2512-9284","position":7,"is_corresponding":false},{"id":805292,"name":"Emma V. Watson","orcid":"0000-0003-1321-6604","position":8,"is_corresponding":false},{"id":241650,"name":"Brenda A. Schulman","orcid":"0000-0002-3083-1126","position":9,"is_corresponding":false},{"id":67,"name":"Philip A. Cole","orcid":"0000-0001-6873-7824","position":10,"is_corresponding":false},{"id":108430,"name":"Stephen J. Elledge","orcid":"0000-0001-7923-6283","position":11,"is_corresponding":false},{"id":1016939,"name":"Christopher Nardone","orcid":"0000-0002-1705-5310","position":0,"is_corresponding":true}],"reference_count":92,"raw_metadata":null,"created_at":"2026-07-19T01:07:22.377587Z","pmid":"36608670","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}