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TMED3 Complex Mediates ER Stress-Associated Secretion of CFTR, Pendrin, and SARS-CoV-2 Spike

 Hak Park  ;  Soo Kyung Seo  ;  Ju-Ri Sim  ;  Su Jin Hwang  ;  Ye Jin Kim  ;  Dong Hoon Shin  ;  Dong Geon Jang  ;  Shin Hye Noh  ;  Pil-Gu Park  ;  Si Hwan Ko  ;  Mi Hwa Shin  ;  Jae Young Choi  ;  Yukishige Ito  ;  Chung-Min Kang  ;  Jae Myun Lee  ;  Min Goo Lee 
 ADVANCED SCIENCE, Vol.9(24) : e2105320, 2022-08 
Journal Title
Issue Date
COVID-19* / metabolism ; Cystic Fibrosis Transmembrane Conductance Regulator* / genetics ; Cystic Fibrosis Transmembrane Conductance Regulator* / metabolism ; Endoplasmic Reticulum Stress* ; Humans ; Protein Transport ; SARS-CoV-2 ; Spike Glycoprotein, Coronavirus* / metabolism ; Sulfate Transporters* / genetics ; Sulfate Transporters* / metabolism ; Vesicular Transport Proteins / metabolism
CFTR ; SARS-CoV-2 spike ; TMED ; UPS ; pendrin
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.
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Appears in Collections:
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Microbiology (미생물학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Otorhinolaryngology (이비인후과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
2. College of Dentistry (치과대학) > Dept. of Pediatric Dentistry (소아치과학교실) > 1. Journal Papers
Yonsei Authors
Kang, Chung Min(강정민) ORCID logo https://orcid.org/0000-0001-7813-3741
Noh, Shin Hye(노신혜) ORCID logo https://orcid.org/0000-0003-3118-9240
Park, Pil Gu(박필구) ORCID logo https://orcid.org/0000-0002-3024-3439
Park, Hak(박학) ORCID logo https://orcid.org/0000-0002-1817-3167
Shin, Dong Hoon(신동훈)
Lee, Min Goo(이민구) ORCID logo https://orcid.org/0000-0001-7436-012X
Lee, Jae Myun(이재면) ORCID logo https://orcid.org/0000-0002-5273-3113
Choi, Jae Young(최재영) ORCID logo https://orcid.org/0000-0001-9493-3458
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