Open AccessTMED3 Complex Mediates ER Stress‐Associated Secretion of CFTR, Pendrin, and SARS‐CoV‐2 Spike
Author(s) -
Park Hak,
Seo Soo Kyung,
Sim JuRi,
Hwang Su Jin,
Kim Ye Jin,
Shin Dong Hoon,
Jang Dong Geon,
Noh Shin Hye,
Park PilGu,
Ko Si Hwan,
Shin Mi Hwa,
Choi Jae Young,
Ito Yukishige,
Kang ChungMin,
Lee Jae Myun,
Lee Min Goo
Publication year - 2022
Publication title -
advanced science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.388
H-Index - 100
ISSN - 2198-3844
DOI - 10.1002/advs.202105320
Subject(s) - transmembrane protein , secretion , microbiology and biotechnology , pendrin , cystic fibrosis transmembrane conductance regulator , golgi apparatus , membrane protein , unfolded protein response , chemistry , transport protein , transmembrane domain , biology , cystic fibrosis , endoplasmic reticulum , biochemistry , transporter , gene , membrane , receptor , genetics
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.