Combined immunodeficiency due to a mutation in the γ1 subunit of the coat protein I complex
Wayne Bainter, … , Victor W. Hsu, Raif S. Geha
Wayne Bainter, … , Victor W. Hsu, Raif S. Geha
Published February 1, 2021
Citation Information: J Clin Invest. 2021;131(3):e140494. https://doi.org/10.1172/JCI140494.
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Combined immunodeficiency due to a mutation in the γ1 subunit of the coat protein I complex

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.

Authors

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

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Figure 1

Homozygous COPG1K652E mutation in the patients.

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Homozygous COPG1K652E mutation in the patients. (A) Family pedigree. (B)...
(A) Family pedigree. (B) Sanger sequencing of the region surrounding the mutation in COPG1 (c.A1954G:p.K652E) in control, mother, and P1. (C) Linear map of γ1-COP. Arrow indicates the location of the K652E missense mutation in the appendage domain. (D) Ribbon diagram of the human γ1-COP appendage domain (aa 608–874) and its N-terminal and C-terminal subdomains. Insets show the potential impact of the mutation on the local interactions between the WT K652 (left) or mutant E652 residue (right) and residues E757 in the N-terminal subdomain, and D762 in the C-terminal subdomain. (E) Representative immunoblot of γ-COP (γ1-COP and γ2-COP) in fibroblasts from P1, P2, and P3 (n = 3) and controls (n = 2) (top) and quantitation of γ1-COP/β-actin and γ1-COP/ γ2-COP ratios in patients relative to controls in 2 independent experiments (bottom). (F) Representative γ-COP (γ1-COP and γ2-COP) and β-COP immunoblot of lysates and of β-COP and IgG control immunoprecipitates, from P2 and control fibroblasts (top) and quantitation of γ1-COP/β-COP ratio in patients relative to controls (n = 2 each) in 3 independent experiments (bottom). Columns and bars represent mean ± SEM.