You are here

Proc Natl Acad Sci U S A DOI:10.1073/pnas.1407001111

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

Publication TypeJournal Article
Year of Publication2014
AuthorsLassen, KG, Kuballa, P, Conway, KL, Patel, KK, Becker, CE, Peloquin, JM, Villablanca, EJ, Norman, JM, Liu, T-C, Heath, RJ, Becker, ML, Fagbami, L, Horn, H, Mercer, J, Yilmaz, ÖH, Jaffe, JD, Shamji, AF, Bhan, AK, Carr, SA, Daly, MJ, Virgin, HW, Schreiber, SL, Stappenbeck, TS, Xavier, RJ
JournalProc Natl Acad Sci U S A
Volume111
Issue21
Pages7741-6
Date Published2014 May 27
ISSN1091-6490
KeywordsAnimals, Autophagy, Blotting, Western, Carrier Proteins, Chromatography, Liquid, Crohn Disease, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Gene Knock-In Techniques, Goblet Cells, Mice, Paneth Cells, Polymorphism, Single Nucleotide, Proteomics, Real-Time Polymerase Chain Reaction, Salmonella Infections, Tandem Mass Spectrometry
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.

DOI10.1073/pnas.1407001111
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/24821797?dopt=Abstract

Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID24821797
PubMed Central IDPMC4040621
Grant ListR01 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