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

Aditya Murthy, Yun Li, Ivan Peng, Mike Reichelt, Anand Kumar Katakam, Rajkumar Noubade, Merone Roose-Girma, Jason DeVoss, Lauri Diehl, Robert R. Graham and Menno van Lookeren Campagne ()
Additional contact information
Aditya Murthy: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA
Yun Li: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA
Ivan Peng: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA
Mike Reichelt: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA
Anand Kumar Katakam: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA
Rajkumar Noubade: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA
Merone Roose-Girma: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA
Jason DeVoss: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA
Lauri Diehl: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA
Robert R. Graham: ITGR Human Genetics, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA
Menno van Lookeren Campagne: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA

Nature, 2014, vol. 506, issue 7489, 456-462

Abstract: 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.

Date: 2014
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DOI: 10.1038/nature13044

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