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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 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-1? 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-1? 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.

SUBMITTER: Lassen KG

PROVIDER: S-EPMC4040621 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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

Lassen Kara G KG Kuballa Petric P Conway Kara L KL Patel Khushbu K KK Becker Christine E CE Peloquin Joanna M JM Villablanca Eduardo J EJ Norman Jason M JM Liu Ta-Chiang TC Heath Robert J RJ Heath Robert J RJ Becker Morgan L ML Fagbami Lola L Horn Heiko H Mercer Johnathan J Yilmaz Omer H OH Jaffe Jacob D JD Shamji Alykhan F AF Bhan Atul K AK Carr Steven A SA Daly Mark J MJ Virgin Herbert W HW Schreiber Stuart L SL Stappenbeck Thaddeus S TS Xavier Ramnik J RJ

Proceedings of the National Academy of Sciences of the United States of America 20140512 21

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 polymorph ...[more]

PMID: 24821797

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Project description:Autophagy-related 16-like 1 (ATG16L1) deficiency leads to impaired cellular autophagy and bacterial degradation as well as an altered cytokine production. The single-nucleotide polymorphism rs2241880 (T300A) is associated with an increased risk for Crohn's disease (CD). ATG16L1 polymorphisms could therefore have an impact on the risk of infectious complications and disease course in CD. We examined the impact of the T300A genotype on the antibacterial response toward a panel of pathogenic bacteria in vitro, as well as clinical infectious complications in vivo and the disease course in a Danish cohort of patients with CD.A total of 236 CD patients were genotyped for ATG16L1(T300A); their clinical records were reviewed, and microbial, radiological, and surgical data were scrutinized. Peripheral blood mononuclear cells (PBMCs) were isolated from healthy controls and CD patients carrying the different ATG16L1 genotypes, and the production of tumor necrosis factor (TNF)-? and interleukin (IL)-1? was measured by enzyme-linked immunosorbent assay after stimulation with a panel of pathogenic bacteria of clinical relevance for the gastrointestinal tract, e.g., enteroinvasive Escherichia coli (EIEC), Listeria monocytogenes, Salmonella typhimurium, Staphylococcus aureus, or Mycobacterium avium paratuberculosis.Fifty-seven healthy controls (15, 29, 13) and 236 patients with CD (50, 108, 78) were genotyped for the T300A ATG16L1 polymorphism (AA homozygous, GG homozygous risk variant, AG heterozygous variant, respectively). The median duration of disease was 128 months (range, 30-175). The cumulative follow-up of this cohort was 2,366 patient-years. ATG16L1 gene variations interfered with the production of IL-1?, which was significantly increased in PBMCs from GG patients in response to all tested bacteria, whereas the TNF-? production was decreased in PBMCs from GG patients stimulated with EIEC, L. monocytogenes, and S. typhimurium, but unaffected by the other bacteria tested. Moreover, the GG variant showed a nonsignificant increase in the risk of bowel resections (P=0.07) and postsurgical infections (P=0.08), whereas the risk of non-disease-related infections was unaffected by genotype in the observation period. In addition, patients with AA and AG variants had a higher frequency of complicated fistulizing disease (P=0.03) with an overall more aggravated disease course with an increased number of surgical procedures for fistulous disease from a median 6.5 operations (2.0 in GG patients; P=0.002). This risk was independent on disease phenotype (penetrating vs. non-penetrating) and immunomodulating medication.The T300A variant in patients with CD strongly increases the risk for complicated fistulizing disease, and significantly affects antibacterial responses in vitro, but the latter effect seems to have a minor role for the infectious risk in CD.

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

Publications

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

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