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

Kara G. Lassen, Petric Kuballa, Kara L. Conway, Khushbu K. Patel, Christine E. Becker, Joanna M. Peloquin, Eduardo J. Villablanca, Jason M. Norman, Ta Chiang Liu, Robert J. Heath, Morgan L. Becker, Lola Fagbami, Heiko Horn, Johnathan Mercer, Omer H. Yilmaz, Jacob D. Jaffe, Alykhan F. Shamji, Atul K. Bhan, Steven A. Carr, Mark J. Daly & 4 others Herbert W. Virgin, Stuart L. Schreiber, Thaddeus S. Stappenbeck, Ramnik J. Xavier

Research output: Contribution to journalArticle

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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 cas-pase 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 typeand pathway-specific disruptions of selective autophagy and suggest a mechanism by which this polymorphism contributes to disease.

Original languageEnglish (US)
Pages (from-to)7741-7746
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number21
DOIs
StatePublished - May 27 2014

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Autophagy
Cytokines
Interleukin-1
Paneth Cells
Caspase 7
Goblet Cells
Essential Genes
Crohn Disease
Proteomics
Proteins
Inflammation

ASJC Scopus subject areas

  • General

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

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, No. 21, 27.05.2014, p. 7741-7746.

Research output: Contribution to journalArticle

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 2014, 'Atg16L1 T300A variant decreases selective autophagy resulting in altered cytokine signaling and decreased antibacterial defense', Proceedings of the National Academy of Sciences of the United States of America, vol. 111, no. 21, pp. 7741-7746. https://doi.org/10.1073/pnas.1407001111
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. / Atg16L1 T300A variant decreases selective autophagy resulting in altered cytokine signaling and decreased antibacterial defense. In: Proceedings of the National Academy of Sciences of the United States of America. 2014 ; Vol. 111, No. 21. pp. 7741-7746.
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title = "Atg16L1 T300A variant decreases selective autophagy resulting in altered cytokine signaling and decreased antibacterial defense",
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 cas-pase 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 typeand pathway-specific disruptions of selective autophagy and suggest a mechanism by which this polymorphism contributes to disease.",
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T1 - Atg16L1 T300A variant decreases selective autophagy resulting in altered cytokine signaling and decreased antibacterial defense

AU - Lassen, Kara G.

AU - Kuballa, Petric

AU - Conway, Kara L.

AU - Patel, Khushbu K.

AU - Becker, Christine E.

AU - Peloquin, Joanna M.

AU - Villablanca, Eduardo J.

AU - Norman, Jason M.

AU - Liu, Ta Chiang

AU - Heath, Robert J.

AU - Becker, Morgan L.

AU - Fagbami, Lola

AU - Horn, Heiko

AU - Mercer, Johnathan

AU - Yilmaz, Omer H.

AU - Jaffe, Jacob D.

AU - Shamji, Alykhan F.

AU - Bhan, Atul K.

AU - Carr, Steven A.

AU - Daly, Mark J.

AU - Virgin, Herbert W.

AU - Schreiber, Stuart L.

AU - Stappenbeck, Thaddeus S.

AU - Xavier, Ramnik J.

PY - 2014/5/27

Y1 - 2014/5/27

N2 - 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 cas-pase 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 typeand pathway-specific disruptions of selective autophagy and suggest a mechanism by which this polymorphism contributes to disease.

AB - 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 cas-pase 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 typeand pathway-specific disruptions of selective autophagy and suggest a mechanism by which this polymorphism contributes to disease.

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DO - 10.1073/pnas.1407001111

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JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

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