한빛사 논문
Wayne Bainter,1 Craig D. Platt,1 Seung-Yeol Park,2,3 Kelsey Stafstrom,1 Jacqueline G. Wallace,1 Zachary T. Peters,1 Michel J. Massaad,1 Michel Becuwe,4 Sandra Andrea Salinas,5 Jennifer Jones,1 Sarah Beaussant-Cohen,1 Faris Jaber,1 Jia-Shu Yang,2 Tobias C. Walther,4 Jordan S. Orange,5 Chitong Rao,6 Seth Rakoff-Nahoum,6 Maria Tsokos,7 Shafiq Ur Rehman Naseem,8 Salem Al-Tamemi,8 Janet Chou,1 Victor W. Hsu,2 and Raif S. Geha1,*
1Division of Immunology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA. 2Division of Rheumatology, Inflammation and Immunity, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA. 3Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk, Republic of Korea. 4Department of Genetics and Complex Diseases and Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA. 5Division of Immunogenetics, Department of Pediatrics, Morgan Stanley Children’s Hospital of New York Presbyterian, Columbia University Irving Medical Center, New York, New York, USA. 6Division of Infectious Diseases, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA. 7Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA. 8Department of Child Health, Sultan Qaboos University Hospital, Muscat, Oman
Authorship note: WB, CDP, and SYP contributed equally to this work.
SAT, JC, VWH, and RSG are equal senior coauthors
*Address correspondence to: Raif S. Geha, Children’s Hospital Boston, 1 Blackfan Circle, Karp 10, Boston, Massachusetts 02115, USA.
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.
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