Regulation of cell surface proteins by CMTM family members

急性肾损伤是人类严重疾病的常见并发症。早期适应性反应知之甚少，因为很难想象受伤后立即发生的修复过程。使用斑马鱼原肾损伤模型，我们确定了几个分子，在迁移修复反应中发挥重要作用，在受伤后立即进行。EpCAM是一种癌症相关的粘附分子，在参与修复过程的细胞中上调。亲和纯化结合质谱分析揭示EpCAM与CMTM家族成员CMTM 6相互作用。CMTM 4和CMTM 6最近被鉴定为PD-L1的调节剂，其允许肿瘤细胞逃避抗肿瘤定向免疫应答。我们发现，CMTM 4和CMTM 6主要表达在斑马鱼pronpehros和后侧线原基（pLLP）。消耗斑马鱼cmtm 4导致缺陷pLLP迁移和Cxcr 4 b的细胞内积累，表明CMTM蛋白更广泛地参与细胞表面蛋白的运输。由于EpCAM和CXCR 4都与肿瘤侵袭和转移有关，我们建议表征CMTM 4和CMTM 6的分子功能，强调它们在细胞迁移和修复反应中的作用。具体来说，我们希望1）确定CMTM蛋白对蛋白质运输和细胞内信号传导的影响，2）确定CMTM蛋白对细胞程序的影响，3）确定CMTM在体内控制表面受体依赖性程序中的作用。总之，这些目标将阐明CMTM 4/6的分子功能，定义它们在细胞表面受体运输调节中的作用，并确定这些分子是否在细胞迁移，修复和肿瘤转移中发挥作用。

Acute kidney injury is frequent complication of severe human disease. The early adaptive responses are poorly understood since it is difficult to visualize the repair processes that occur immediately after an injury. Using the zebrafish pronephros injury model, we identified several molecules that play an essential role in the migratory repair response that ensues immediately after an injury. EpCAM, a cancer-associated adhesion molecule, is up-regulated in cells participating in the repair process. Affinity-purification in combination with mass spectrometry revealed that EpCAM interacts with the CMTM family member CMTM6. CMTM4 and CMTM6 have recently been identified as regulators of PD-L1, which allows tumor cells to escape an anti-tumor directed immune response. We found that CMTM4 and CMTM6 are predominantly expressed in the zebrafish pronpehros and the posterior lateral line primordium (pLLP). Depletion of zebrafish cmtm4 resulted in defective pLLP migration and intracellular accumulation of Cxcr4b, suggesting that CMTM proteins are more broadly involved in the trafficking of cell surface proteins. Since both EpCAM and CXCR4 have been implicated in tumor invasion and metastasis, we propose to characterize the molecular functions of CMTM4 and CMTM6, emphasizing their role in cell migration and repair responses. Specifically, we want to 1) determine the impact of CMTM proteins on protein trafficking and intracellular signaling, 2) determine the impact of CMTM proteins on cellular programs, and 3) determine the role of CMTMs in controlling surface receptor-dependent programs in vivo. Together, these aims will elucidate the molecular functions of CMTM4/6, define their role in the regulation of cell surface receptor trafficking, and determine whether these molecules play a role in cell migration, repair and tumor metastasis.