Recruitment of folliculin to lysosomes supports the amino acid-dependent activation of Rag GTPases

J Cell Biol. 2013 Sep 30;202(7):1107-22. doi: 10.1083/jcb.201307084.

Abstract

Birt-Hogg-Dubé syndrome, a human disease characterized by fibrofolliculomas (hair follicle tumors) as well as a strong predisposition toward the development of pneumothorax, pulmonary cysts, and renal carcinoma, arises from loss-of-function mutations in the folliculin (FLCN) gene. In this study, we show that FLCN regulates lysosome function by promoting the mTORC1-dependent phosphorylation and cytoplasmic sequestration of transcription factor EB (TFEB). Our results indicate that FLCN is specifically required for the amino acid-stimulated recruitment of mTORC1 to lysosomes by Rag GTPases. We further demonstrated that FLCN itself was selectively recruited to the surface of lysosomes after amino acid depletion and directly bound to RagA via its GTPase domain. FLCN-interacting protein 1 (FNIP1) promotes both the lysosome recruitment and Rag interactions of FLCN. These new findings define the lysosome as a site of action for FLCN and indicate a critical role for FLCN in the amino acid-dependent activation of mTOR via its direct interaction with the RagA/B GTPases.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / metabolism
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism*
  • Blotting, Western
  • Carrier Proteins / metabolism*
  • Cytoplasm / metabolism
  • Fluorescent Antibody Technique
  • Humans
  • Immunoprecipitation
  • Lysosomes / metabolism*
  • Mechanistic Target of Rapamycin Complex 1
  • Monomeric GTP-Binding Proteins / metabolism*
  • Multiprotein Complexes / metabolism*
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • RNA, Small Interfering / genetics
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • TOR Serine-Threonine Kinases / metabolism*
  • Tumor Suppressor Proteins / antagonists & inhibitors
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*

Substances

  • Amino Acids
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Carrier Proteins
  • FLCN protein, human
  • FNIP1 protein, human
  • Multiprotein Complexes
  • Proto-Oncogene Proteins
  • RNA, Small Interfering
  • Recombinant Proteins
  • TFEB protein, human
  • Tumor Suppressor Proteins
  • Mechanistic Target of Rapamycin Complex 1
  • TOR Serine-Threonine Kinases
  • Monomeric GTP-Binding Proteins