Atg16L1 T300A variant decreases selective autophagy resulting in altered cytokine signaling and decreased antibacterial defense

KG Lassen, P Kuballa, KL Conway… - Proceedings of the …, 2014 - National Acad Sciences
KG Lassen, P Kuballa, KL Conway, KK Patel, CE Becker, JM Peloquin, EJ Villablanca
Proceedings of the National Academy of Sciences, 2014National Acad Sciences
A coding polymorphism (Thr300Ala) in the essential autophagy gene, autophagy related 16-
like 1 (ATG16L1), confers increased risk for the development of Crohn disease, although the
mechanisms by which single disease-associated polymorphisms contribute to pathogenesis
have been difficult to dissect given that environmental factors likely influence disease
initiation in these patients. Here we introduce a knock-in mouse model expressing the
Atg16L1 T300A variant. Consistent with the human polymorphism, T300A knock-in mice do …
A coding polymorphism (Thr300Ala) in the essential autophagy gene, autophagy related 16-like 1 (ATG16L1), confers increased risk for the development of Crohn disease, although the mechanisms by which single disease-associated polymorphisms contribute to pathogenesis have been difficult to dissect given that environmental factors likely influence disease initiation in these patients. Here we introduce a knock-in mouse model expressing the Atg16L1 T300A variant. Consistent with the human polymorphism, T300A knock-in mice do not develop spontaneous intestinal inflammation, but exhibit morphological defects in Paneth and goblet cells. Selective autophagy is reduced in multiple cell types from T300A knock-in mice compared with WT mice. The T300A polymorphism significantly increases caspase 3- and caspase 7-mediated cleavage of Atg16L1, resulting in lower levels of full-length Atg16Ll T300A protein. Moreover, Atg16L1 T300A is associated with decreased antibacterial autophagy and increased IL-1β production in primary cells and in vivo. Quantitative proteomics for protein interactors of ATG16L1 identified previously unknown nonoverlapping sets of proteins involved in ATG16L1-dependent antibacterial autophagy or IL-1β production. These findings demonstrate how the T300A polymorphism leads to cell type- and pathway-specific disruptions of selective autophagy and suggest a mechanism by which this polymorphism contributes to disease.
National Acad Sciences