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.
Wayne Bainter, Craig D. Platt, Seung-Yeol Park, Kelsey Stafstrom, Jacqueline G. Wallace, Zachary T. Peters, Michel J. Massaad, Michel Becuwe, Sandra Andrea Salinas, Jennifer Jones, Sarah Beaussant-Cohen, Faris Jaber, Jia-Shu Yang, Tobias C. Walther, Jordan S. Orange, Chitong Rao, Seth Rakoff-Nahoum, Maria Tsokos, Shafiq Ur Rehman Naseem, Salem Al-Tamemi, Janet Chou, Victor W. Hsu, Raif S. Geha