TMEM127基因编码一种功能不甚明确的跨膜蛋白，该基因在肾上腺髓质起源的嗜铬细胞瘤（pheochromocytomas）中发生突变。在这里，我们报告了单核分辨率下，TMEM127突变肿瘤与携带酪氨酸激酶受体RET突变的嗜铬细胞瘤共享前体细胞和转录调控元件。此外，TMEM127突变的pheochromocytomas、人类细胞以及TMEM127小鼠敲除模型中蓄积RET并增强其信号传导。TMEM127对RET细胞定位、内流和溶酶体介导的降解具有贡献。从机制上讲，TMEM127结合RET并招募NEDD4 E3泛素连接酶，通过TMEM127 C端PxxY基元对RET进行泛素化和降解。最后，TMEM127失活后细胞增殖和肿瘤负担的增加可以在体外和体内通过选择性RET抑制剂逆转。我们的结果定义TMEM127为泛素系统的组成部分，并确定异常RET稳定化作为TMEM127功能丧失突变导致嗜铬细胞瘤的可能机制。 版权所有©2023 The Authors，由Elsevier Inc. 发表。保留所有权利。

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.Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.