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Nature. 2014 Feb 27;506(7489):456-62. doi: 10.1038/nature13044. Epub 2014 Feb 19.

A Crohn's disease variant in Atg16l1 enhances its degradation by caspase 3.

Author information

1
Department of Immunology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
2
Department of Pathology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
3
Department of Molecular Biology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
4
ITGR Human Genetics, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.

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.

PMID:
24553140
DOI:
10.1038/nature13044
[Indexed for MEDLINE]

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