|Publication Type||Journal Article|
|Year of Publication||2014|
|Authors||Lassen, KG, Kuballa, P, Conway, KL, Patel, KK, Becker, CE, Peloquin, JM, Villablanca, EJ, Norman, JM, Liu, TC, Heath, RJ, Becker, ML, Fagbami, L, Horn, H, Mercer, J, Yilmaz, OH, Jaffe, JD, Shamji, AF, Bhan, AK, Carr, SA, Daly, MJ, Virgin, HW, Schreiber, SL, Stappenbeck, TS, Xavier, RJ|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
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.