Atg16L1 T300A variant decreases selective autophagy resulting in altered cytokine signaling and decreased antibacterial defense
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Author
Lassen, Kara G.
Kuballa, Petric
Conway, Kara L.
Patel, Khushbu K.
Becker, Christine E.
Peloquin, Joanna M.
Villablanca, Eduardo J.
Norman, Jason M.
Liu, Ta-Chiang
Heath, Robert J.
Becker, Morgan L.
Fagbami, Lola
Horn, Heiko
Mercer, Johnathan
Yilmaz, 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.
Published Version
https://doi.org/10.1073/pnas.1407001111Metadata
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Lassen, 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.Abstract
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-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.Terms of Use
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