A central role for regulated protein stability in the control of TFE3 and MITF by nutrients.
Mol Cell
; 83(1): 57-73.e9, 2023 01 05.
Article
en En
| MEDLINE
| ID: mdl-36608670
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 CUL1ß-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.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Factor de Transcripción Asociado a Microftalmía
/
Aminoácidos
Límite:
Animals
Idioma:
En
Año:
2023
Tipo del documento:
Article