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Atg16L1 T300A variant decreases selective autophagy resulting in altered cytokine signaling and decreased antibacterial defense

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... Full description

1st Person: Lassen, Kara G.
Additional Persons: 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.
Source: in Proceedings of the National Academy of Sciences of the United States of America Vol. 111, No. 21 (2014), p. 7741-7746
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Type of Publication: Article
Language: English
Published: 2014
Online: Volltext
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100 1 |a Lassen, Kara G. 
245 1 0 |a Atg16L1 T300A variant decreases selective autophagy resulting in altered cytokine signaling and decreased antibacterial defense  |h Elektronische Ressource 
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500 |a Copyright: copyright © 1993–2008 National Academy of Sciences of the Uinted States of America 
520 |a 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 ATG16L1dependent antibacterial autophagy or IL-1β production. These findings demonstrate how the T300A polymorphism leads to cell typeand pathway-specific disruptions of selective autophagy and suggest a mechanism by which this polymorphism contributes to disease. 
611 2 7 |a research-article  |2 gnd 
689 0 0 |A f  |a research-article 
689 0 |5 DE-601 
700 1 |a Kuballa, Petric 
700 1 |a Conway, Kara L. 
700 1 |a Patel, Khushbu K. 
700 1 |a Becker, Christine E. 
700 1 |a Peloquin, Joanna M. 
700 1 |a Villablanca, Eduardo J. 
700 1 |a Norman, Jason M. 
700 1 |a Liu, Ta-Chiang 
700 1 |a Heath, Robert J. 
700 1 |a Becker, Morgan L. 
700 1 |a Fagbami, Lola 
700 1 |a Horn, Heiko 
700 1 |a Mercer, Johnathan 
700 1 |a Yilmaz, Omer H. 
700 1 |a Jaffe, Jacob D. 
700 1 |a Shamji, Alykhan F. 
700 1 |a Bhan, Atul K. 
700 1 |a Carr, Steven A. 
700 1 |a Daly, Mark J. 
700 1 |a Virgin, Herbert W. 
700 1 |a Schreiber, Stuart L. 
700 1 |a Stappenbeck, Thaddeus S. 
700 1 |a Xavier, Ramnik J. 
773 0 8 |i in  |t Proceedings of the National Academy of Sciences of the United States of America  |g Vol. 111, No. 21 (2014), p. 7741-7746  |q 111:21<7741-7746  |w (DE-601)JST069399220  |x 1091-6490 
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951 |a AR 
952 |d 111  |j 2014  |e 21  |h 7741-7746 

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