cancel
Showing results for 
Search instead for 
Did you mean: 
Orbitrap_SciLib
Reputable Mentor II
Reputable Mentor II
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.
Proc Natl Acad Sci U S A. 2014 May 27;111(21):7741-6. doi: 10.1073/pnas.1407001111. Epub 2014 May 12.
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.

http://www.pnas.org/content/111/21/7741.long
Massachusetts General Hospital, Harvard Medical School, Washington University School of Medicine, Massachusetts Institute of Technology, Broad Institute
Version history
Last update:
‎10-15-2021 11:35 AM
Updated by:
Closed Account
Contributors