Combined immunodeficiency due to a mutation in the γ1 subunit of the coat protein I complex.
J Clin Invest
; 131(3)2021 02 01.
Article
en En
| MEDLINE
| ID: mdl-33529166
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Linfocitos B
/
Activación de Linfocitos
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Linfocitos T
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Inmunodeficiencia Combinada Grave
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Apoptosis
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Mutación Missense
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Estrés del Retículo Endoplásmico
Límite:
Animals
/
Humans
Idioma:
En
Revista:
J Clin Invest
Año:
2021
Tipo del documento:
Article
País de afiliación:
Estados Unidos