Combined immunodeficiency due to a mutation in the γ1 subunit of the coat protein I complex
Journal
Journal of Clinical Investigation
Journal Volume
131
Journal Issue
3
Date Issued
2021
Author(s)
Bainter W
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. Copyright ? 2021, American Society for Clinical Investigation.
Subjects
chaperone; coat protein complex I; coat protein complex I gamma; taurursodiol; unclassified drug; adaptive immunity; antibody response; apoptosis; Article; B lymphocyte; body weight loss; cell proliferation; child; clinical article; combined immunodeficiency; controlled study; endoplasmic reticulum stress; gene mutation; genetic association; homeostasis; homozygosity; human; infant; information retrieval; lymphocytopenia; phenotype; preschool child; priority journal; protein function; school child; T lymphocyte
Type
journal article