An mTORC1-mediated negative feedback loop constrains amino acid-induced FLCN-Rag activation in renal cells with TSC2 loss
Abstract
The mechanistic target of rapamycin complex 1 (mTORC1) integrates inputs from growth factors and nutrients, but how mTORC1 autoregulates its activity remains unclear. The MiT/TFE transcription factors are phosphorylated and inactivated by mTORC1 following lysosomal recruitment by RagC/D GTPases in response to amino acid stimulation. We find that starvation-induced lysosomal localization of the RagC/D GAP complex, FLCN:FNIP2, is markedly impaired in a mTORC1-sensitive manner in renal cells with TSC2 loss, resulting in unexpected TFEB hypophosphorylation and activation upon feeding. TFEB phosphorylation in TSC2-null renal cells is partially restored by destabilization of the lysosomal folliculin complex (LFC) induced by FLCN mutants and is fully rescued by forced lysosomal localization of the FLCN:FNIP2 dimer. Our data indicate that a negative feedback loop constrains amino acid-induced, FLCN:FNIP2-mediated RagC activity in renal cells with constitutive mTORC1 signaling, and the resulting MiT/TFE hyperactivation may drive oncogenesis with loss of the TSC2 tumor suppressor.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Nov 10, 2022
- Source ID
- 10.1038/s41467-022-34617-7
Entities
People
- Adrianna A. Mendes
- Brandon Lam
- Clarence Rachel Villanueva
- Daniela C Salles
- Ethan Schaffer
- Hans B Liu
- Juhyung Woo
- Kaushal Asrani
- Kewen Feng
- Lia Oliveira
- Pedram Argani
- Sanjana Murali
- Tamara L Lotan
- Thiago Vidotto
Organizations
- Congressionally Directed Medical Research Programs
- National Cancer Institute
- United States Department of Health and Human Services