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Crohn's Disease Forum » Books, Multimedia, Research & News » A Crohn’s disease variant in Atg16l1 enhances its degradation by caspase 3


02-22-2014, 09:33 AM   #1
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A Crohn’s disease variant in Atg16l1 enhances its degradation by caspase 3

http://www.nature.com/nature/journal...ture13044.html

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

Nature (2014)

Aditya Murthy, Yun Li. Ivan Peng, Mike Reichelt, Anand Kumar Katakam, Rajkumar Noubade, Merone Roose-Girma, Jason DeVoss, auri Diehl, Robert R. Graham & Menno van Lookeren Campagne

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.
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