The TMEM127 human tumor suppressor is a component of the mTORC1 lysosomal nutrient-sensing complex

Area of Science:

• Cell Biology
• Molecular Oncology
• Signal Transduction

Background:

• The TMEM127 tumor suppressor gene is frequently mutated in pheochromocytomas, leading to increased mTORC1 signaling through unknown mechanisms.
• TMEM127 encodes a transmembrane protein whose function in cancer development remains largely uncharacterized.

Purpose of the Study:

• To elucidate the molecular mechanisms by which TMEM127 regulates mTORC1 signaling.
• To investigate the interaction of TMEM127 with key components of the mTORC1 pathway at the lysosome.

Main Methods:

• Co-immunoprecipitation assays to identify TMEM127 interacting partners.
• Analysis of mTORC1 pathway activation in TMEM127-deficient cells and tumors.
• Cellular localization studies of TMEM127 and associated proteins.

Main Results:

• TMEM127 directly interacts with the lysosome-anchored Rag GTPase-LAMTOR-vATPase complex, which mediates amino acid-dependent mTORC1 activation.
• TMEM127 expression inhibits mTORC1 recruitment to Rag GTPases under nutrient-rich conditions.
• Loss of TMEM127 results in accumulation of LAMTOR proteins in the lysosome and increased mTORC1 signaling, observed in both cellular models and patient tumors.

Conclusions:

• TMEM127 functions as a negative regulator of mTORC1 signaling by modulating the lysosomal Ragulator complex.
• These findings explain the heightened mTORC1 activation in TMEM127-deficient tumors and highlight TMEM127's role in tumor suppression.