Combined immunodeficiency due to a mutation in the γ1 subunit of the coat protein I complex

• Published in: The Journal of clinical investigation Vol. 131; no. 3; pp. 1 - 17
• Main 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
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.02.2021
• Subjects: Adaptive immunity; Antibodies; Apoptosis; Biomedical research; Cell proliferation; Cell-mediated immunity; Chaperones; Coat protein; Cytokines; Endoplasmic reticulum; Golgi apparatus; Hepatitis; Homeostasis; Humoral immunity; Immunodeficiency; Immunoglobulins; Kinases; Lymphocytes; Lymphocytes B; Lymphocytes T; Lymphopenia; Mutants; Mutation; Phenotypes; Proteins; Streptococcus infections; Tauroursodeoxycholic acid; Transcription factors; Viral infections; Adaptive immunity; Immunology
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI140494

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.