Atg16L1 T300A variant decreases selective autophagy resulting in altered cytokine signaling and decreased antibacterial defense.
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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-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. |
Year of Publication | 2014
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Journal | Proc Natl Acad Sci U S A
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Volume | 111
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Issue | 21
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Pages | 7741-6
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Date Published | 2014 May 27
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ISSN | 1091-6490
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DOI | 10.1073/pnas.1407001111
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PubMed ID | 24821797
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PubMed Central ID | PMC4040621
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Grant list | R01 AI084887 / AI / NIAID NIH HHS / United States
DK043351 / DK / NIDDK NIH HHS / United States
AI084887 / AI / NIAID NIH HHS / United States
P30 DK043351 / DK / NIDDK NIH HHS / United States
K99 AG045144 / AG / NIA NIH HHS / United States
T32 AI007163 / AI / NIAID NIH HHS / United States
R00 AG045144 / AG / NIA NIH HHS / United States
DK097485 / DK / NIDDK NIH HHS / United States
R01 DK097485 / DK / NIDDK NIH HHS / United States
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