Combined immunodeficiency due to a mutation in the γ1 subunit of the coat protein I complex
SCIE
SCOPUS
- Title
- Combined immunodeficiency due to a mutation in the γ1 subunit of the coat protein I complex
- Authors
- Bainter, Wayne; Platt, Craig D.; Park, Seung-Yeol; Stafstrom, Kelsey; Wallace, Jacqueline G.; Peters, Zachary T.; Massaad, Michel J.; Becuwe, Michel; Salinas, Sandra Andrea; Jones, Jennifer; Beaussant-Cohen, Sarah; Jaber, Faris; Yang, Jia-Shu; Walther, Tobias C.; Orange, Jordan S.; Rao, Chitong; Rakoff-Nahoum, Seth; Tsokos, Maria; Naseem, Shafiq Ur Rehman; Al-Tamemi, Salem; Chou, Janet; Hsu, Victor W.; Geha, Raif S.
- Date Issued
- 2021-02
- Publisher
- American Society for Clinical Investigation
- Abstract
- The coat protein I (COPI) complex mediates retrograde trafficking from the Golgi to the endoplasmic reticulum (ER). Five siblings with persistent bacterial and viral infections and defective humoral and cellular immunity had a homozygous p.K652E mutation in the γ1 subunit of COPI (γ1-COP). The mutation disrupts COPI binding to the KDEL receptor and impairs the retrieval of KDEL-bearing chaperones from the Golgi to the ER. Homozygous Copg1K652E mice had increased ER stress in activated T and B cells, poor antibody responses, and normal numbers of T cells that proliferated normally, but underwent increased apoptosis upon activation. Exposure of the mutants to pet store mice caused weight loss, lymphopenia, and defective T cell proliferation that recapitulated the findings in the patients. The ER stress-relieving agent tauroursodeoxycholic acid corrected the immune defects of the mutants and reversed the phenotype they acquired following exposure to pet store mice. This study establishes the role of γ1-COP in the ER retrieval of KDEL-bearing chaperones and thereby the importance of ER homeostasis in adaptive immunity.
- URI
- https://oasis.postech.ac.kr/handle/2014.oak/105191
- DOI
- 10.1172/JCI140494
- ISSN
- 0021-9738
- Article Type
- Article
- Citation
- Journal of Clinical Investigation, vol. 131, no. 3, 2021-02
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