TMEM127 suppresses tumor development by promoting RET ubiquitination, positioning, and degradation

The TMEM127 gene encodes a transmembrane protein of poorly known function that is mutated in pheochromocytomas, neural crest-derived tumors of adrenomedullary cells. Here, we report that, at single-nucleus resolution, TMEM127-mutant tumors share precursor cells and transcription regulatory elements with pheochromocytomas carrying mutations of the tyrosine kinase receptor RET. Additionally, TMEM127-mutant pheochromocytomas, human cells, and mouse knockout models of TMEM127 accumulate RET and increase its signaling. TMEM127 contributes to RET cellular positioning, trafficking, and lysosome-mediated degradation. Mechanistically, TMEM127 binds to RET and recruits the NEDD4 E3 ubiquitin ligase for RET ubiquitination and degradation via TMEM127 C-terminal PxxY motifs. Lastly, increased cell proliferation and tumor burden after TMEM127 loss can be reversed by selective RET inhibitors in vitro and in vivo. Our results define TMEM127 as a component of the ubiquitin system and identify aberrant RET stabilization as a likely mechanism through which TMEM127 loss-of-function mutations cause pheochromocytoma.

Automated summary

TMEM127 gene mutation leads to pheochromocytomas, and the mutated tumors share precursor cells and transcription regulatory elements with pheochromocytomas carrying RET mutations. In addition, TMEM127 mutation results in the accumulation and increased signaling of RET, and TMEM127 contributes to RET cellular positioning, trafficking, and degradation. This study helps to understand the role of TMEM127 in the development of pheochromocytomas.