Human ALPI deficiency causes inflammatory bowel disease and highlights a key mechanism of gut homeostasis - CNRS - Centre national de la recherche scientifique Accéder directement au contenu
Article Dans Une Revue EMBO Molecular Medicine Année : 2018

Human ALPI deficiency causes inflammatory bowel disease and highlights a key mechanism of gut homeostasis

Résumé

Herein, we report the first identification of biallelic-inherited mutations inALPIas a Mendelian cause of inflammatory bowel disease in two unrelated patients.ALPIencodes for intestinal phosphatase alkaline, a brush border metalloenzyme that hydrolyses phosphate from the lipid A moiety of lipopolysaccharides and thereby drastically reduces Toll-like receptor 4 agonist activity. Prediction tools and structural modelling indicate that all mutations affect critical residues or inter-subunit interactions, and heterologous expression in HEK293T cells demonstrated that allALPImutations were loss of function.ALPImutations impaired either stability or catalytic activity of ALPI and rendered it unable to detoxify lipopolysaccharide-dependent signalling. Furthermore, ALPI expression was reduced in patients' biopsies, and ALPI activity was undetectable in ALPI-deficient patient's stool. Our findings highlight the crucial role of ALPI in regulating host-microbiota interactions and restraining host inflammatory responses. These results indicate thatALPImutations should be included in screening for monogenic causes of inflammatory bowel diseases and lay the groundwork for ALPI-based treatments in intestinal inflammatory disorders.

Dates et versions

hal-02183255 , version 1 (15-07-2019)

Identifiants

Citer

Marianna Parlato, Fabienne Charbit-Henrion, Jie Pan, Claudio Romano, Rémi Duclaux-Loras, et al.. Human ALPI deficiency causes inflammatory bowel disease and highlights a key mechanism of gut homeostasis. EMBO Molecular Medicine, 2018, 10 (4), pii: e8483. ⟨10.15252/emmm.201708483⟩. ⟨hal-02183255⟩
47 Consultations
0 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More