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The tumor susceptibility gene TMEM127 is mutated in renal cell carcinomas and modulates endolysosomal function
1Department of Medicine.
Abstract:
TMEM127 is an endosome-associated tumor suppressor gene in pheochromocytomas, neuroendocrine tumors that can co-occur with renal cell carcinomas (RCCs). TMEM127 loss leads to increased mTOR signaling. However, the spectrum of tumors with TMEM127 mutation and how TMEM127 and mTOR interact in tumorigenesis remains unknown. Here, we report that germline TMEM127 mutations occur in RCCs and that some mutant proteins, unlike wild-type (WT) TMEM127, fail to cooperate with activated early endosomal GTPase, Rab5, to inhibit mTOR signaling. Tmem127-null mouse embryonic fibroblasts (MEFs) are deficient in generating early-to-late hybrid endosomes upon constitutive Rab5 activation, a defect rescued by WT, but not mutant, TMEM127. This endosomal dysfunction results in diminished mTOR colocalization with Rab5-positive vesicles. Conversely, active, lysosomal-bound mTOR is increased in Tmem127-null MEFs, which also display enhanced lysosomal biogenesis. Our data map the tumor-suppressive properties of TMEM127 to modulation of mTOR function in the endolysosome, a feature that may contribute to both pheochromocytoma and RCC pathogenesis.
Insights
Germline TMEM127 mutations are found in renal cell carcinomas (RCCs). TMEM127 loss disrupts endosomal mTOR signaling, potentially contributing to RCC and pheochromocytoma development.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- TMEM127 is an endosome-associated tumor suppressor gene.
- Loss of TMEM127 function is linked to increased mTOR signaling.
- TMEM127's role in various cancers and its interaction with mTOR is not fully understood.
Purpose of the Study:
- To investigate the occurrence of TMEM127 mutations in renal cell carcinomas (RCCs).
- To elucidate the mechanism by which TMEM127 and mTOR interact in tumorigenesis.
- To determine how TMEM127 mutations affect endosomal trafficking and mTOR signaling.
Main Methods:
- Analysis of germline TMEM127 mutations in RCC patients.
- Utilizing Tmem127-null mouse embryonic fibroblasts (MEFs) to study endosomal function.
- Assessing mTOR signaling and its colocalization with endosomal markers.
Main Results:
- Germline TMEM127 mutations were identified in RCCs.
- Mutant TMEM127 proteins failed to inhibit mTOR signaling in cooperation with Rab5.
- Tmem127-null MEFs exhibited defects in hybrid endosome formation and altered mTOR localization.
Conclusions:
- TMEM127's tumor-suppressive function is linked to its modulation of mTOR signaling within the endolysosome.
- Dysfunctional endosomal trafficking due to TMEM127 mutations contributes to aberrant mTOR activity.
- These findings suggest a role for TMEM127 in both pheochromocytoma and RCC pathogenesis.
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