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A Crohn's disease variant in Atg16l1 enhances its degradation by caspase 3.
- Source :
-
Nature [Nature] 2014 Feb 27; Vol. 506 (7489), pp. 456-62. Date of Electronic Publication: 2014 Feb 19. - Publication Year :
- 2014
-
Abstract
- Crohn's disease is a debilitating inflammatory bowel disease (IBD) that can involve the entire digestive tract. A single-nucleotide polymorphism (SNP) encoding a missense variant in the autophagy gene ATG16L1 (rs2241880, Thr300Ala) is strongly associated with the incidence of Crohn's disease. Numerous studies have demonstrated the effect of ATG16L1 deletion or deficiency; however, the molecular consequences of the Thr300Ala (T300A) variant remains unknown. Here we show that amino acids 296-299 constitute a caspase cleavage motif in ATG16L1 and that the T300A variant (T316A in mice) significantly increases ATG16L1 sensitization to caspase-3-mediated processing. We observed that death-receptor activation or starvation-induced metabolic stress in human and murine macrophages increased degradation of the T300A or T316A variants of ATG16L1, respectively, resulting in diminished autophagy. Knock-in mice harbouring the T316A variant showed defective clearance of the ileal pathogen Yersinia enterocolitica and an elevated inflammatory cytokine response. In turn, deletion of the caspase-3-encoding gene, Casp3, or elimination of the caspase cleavage site by site-directed mutagenesis rescued starvation-induced autophagy and pathogen clearance, respectively. These findings demonstrate that caspase 3 activation in the presence of a common risk allele leads to accelerated degradation of ATG16L1, placing cellular stress, apoptotic stimuli and impaired autophagy in a unified pathway that predisposes to Crohn's disease.
- Subjects :
- Amino Acid Motifs
Animals
Autophagy genetics
Autophagy-Related Proteins
Carrier Proteins chemistry
Caspase 3 deficiency
Caspase 3 genetics
Cell Line
Cells, Cultured
Crohn Disease pathology
Cytokines immunology
Enzyme Activation
Female
Food Deprivation
Humans
Macrophages immunology
Macrophages metabolism
Male
Mice
Mice, Inbred C57BL
Mutagenesis, Site-Directed
Stress, Physiological
Yersinia enterocolitica immunology
Carrier Proteins genetics
Carrier Proteins metabolism
Caspase 3 metabolism
Crohn Disease genetics
Polymorphism, Single Nucleotide genetics
Proteolysis
Subjects
Details
- Language :
- English
- ISSN :
- 1476-4687
- Volume :
- 506
- Issue :
- 7489
- Database :
- MEDLINE
- Journal :
- Nature
- Publication Type :
- Academic Journal
- Accession number :
- 24553140
- Full Text :
- https://doi.org/10.1038/nature13044