Lassen, Kara G.Kuballa, PetricConway, Kara L.Patel, Khushbu K.Becker, Christine E.Peloquin, Joanna M.Villablanca, Eduardo J.Norman, Jason M.Liu, Ta-ChiangHeath, Robert J.Becker, Morgan L.Fagbami, LolaHorn, HeikoMercer, JohnathanYilmaz, Omer H.Jaffe, Jacob D.Shamji, Alykhan F.Bhan, Atul K.Carr, Steven A.Daly, Mark J.Virgin, Herbert W.Schreiber, Stuart L.Stappenbeck, Thaddeus S.Xavier, Ramnik J.2019-10-032014Lassen, K. G., P. Kuballa, K. L. Conway, K. K. Patel, C. E. Becker, J. M. Peloquin, E. J. Villablanca, et al. 2014. “Atg16L1 T300A Variant Decreases Selective Autophagy Resulting in Altered Cytokine Signaling and Decreased Antibacterial Defense.” Proceedings of the National Academy of Sciences 111 (21): 7741–46. https://doi.org/10.1073/pnas.1407001111.0027-84240744-28311091-6490http://nrs.harvard.edu/urn-3:HUL.InstRepos:41461196A 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-1 beta 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-1 beta 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.en-USJournal Article2019-10-0310.1073/pnas.1407001111