Department of Pharmacology, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, 03722, Korea.
Department of Laboratory Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, 03722, Korea.
Adv Sci (Weinh). 2022 Aug;9(24):e2105320. doi: 10.1002/advs.202105320. Epub 2022 Jun 24.
Under ER stress conditions, the ER form of transmembrane proteins can reach the plasma membrane via a Golgi-independent unconventional protein secretion (UPS) pathway. However, the targeting mechanisms of membrane proteins for UPS are unknown. Here, this study reports that TMED proteins play a critical role in the ER stress-associated UPS of transmembrane proteins. The gene silencing results reveal that TMED2, TMED3, TMED9 and TMED10 are involved in the UPS of transmembrane proteins, such as CFTR, pendrin and SARS-CoV-2 Spike. Subsequent mechanistic analyses indicate that TMED3 recognizes the ER core-glycosylated protein cargos and that the heteromeric TMED2/3/9/10 complex mediates their UPS. Co-expression of all four TMEDs improves, while each single expression reduces, the UPS and ion transport function of trafficking-deficient ΔF508-CFTR and p.H723R-pendrin, which cause cystic fibrosis and Pendred syndrome, respectively. In contrast, TMED2/3/9/10 silencing reduces SARS-CoV-2 viral release. These results provide evidence for a common role of TMED3 and related TMEDs in the ER stress-associated, Golgi-independent secretion of transmembrane proteins.
在 ER 应激条件下，跨膜蛋白的 ER 形式可以通过高尔基体非依赖的非常规蛋白分泌 (UPS) 途径到达质膜。然而，膜蛋白 UPS 的靶向机制尚不清楚。本研究报道 TMED 蛋白在跨膜蛋白 ER 应激相关 UPS 中发挥关键作用。基因沉默结果表明，TMED2、TMED3、TMED9 和 TMED10 参与跨膜蛋白的 UPS，如 CFTR、pendrin 和 SARS-CoV-2 Spike。随后的机制分析表明，TMED3 识别 ER 核心糖基化蛋白货物，异源 TMED2/3/9/10 复合物介导其 UPS。所有四个 TMED 的共表达可改善转运缺陷型 ΔF508-CFTR 和 p.H723R-pendrin 的 UPS 和离子转运功能，而每个单独的表达则降低，这两种蛋白分别导致囊性纤维化和 Pendred 综合征。相反，TMED2/3/9/10 的沉默会降低 SARS-CoV-2 病毒的释放。这些结果为 TMED3 和相关 TMED 蛋白在跨膜蛋白 ER 应激相关、高尔基体非依赖分泌中的共同作用提供了证据。
