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ATG16L1: A multifunctional susceptibility factor in Crohn disease.

ABSTRACT: Genetic variations in the autophagic pathway influence genetic predispositions to Crohn disease. Autophagy, the major lysosomal pathway for degrading and recycling cytoplasmic material, constitutes an important homeostatic cellular process. Of interest, single-nucleotide polymorphisms in ATG16L1 (autophagy-related 16-like 1 [S. cerevisiae]), a key component in the autophagic response to invading pathogens, have been associated with an increased risk of developing Crohn disease. The most common and well-studied genetic variant of ATG16L1 (rs2241880; leading to a T300A conversion) exhibits a strong association with risk for developing Crohn disease. The rs2241880 variant plays a crucial role in pathogen clearance, resulting in imbalanced cytokine production, and is linked to other biological processes, such as the endoplasmic reticulum stress/unfolded protein response. In this review, we focus on the importance of ATG16L1 and its genetic variant (T300A) within the elementary biological processes linked to Crohn disease.

SUBMITTER: Salem M

PROVIDER: S-EPMC4502774 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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ATG16L1: A multifunctional susceptibility factor in Crohn disease.

Salem Mohammad M Ammitzboell Mette M Nys Kris K Seidelin Jakob Benedict JB Nielsen Ole Haagen OH

Autophagy 20150401 4

Genetic variations in the autophagic pathway influence genetic predispositions to Crohn disease. Autophagy, the major lysosomal pathway for degrading and recycling cytoplasmic material, constitutes an important homeostatic cellular process. Of interest, single-nucleotide polymorphisms in ATG16L1 (autophagy-related 16-like 1 [S. cerevisiae]), a key component in the autophagic response to invading pathogens, have been associated with an increased risk of developing Crohn disease. The most common a ...[more]

PMID: 25906181

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Project description:Purpose:A significant feature of pediatric inflammatory bowel diseases (IBD), which include Crohn disease (CD), and ulcerative colitis (UC), is failure to suppress inflammation. The inability to regulate inflammation renders a major challenge toward establishing effective treatments in IBD. Nuclear factor kappa-light-chain-enhancer of activated B-cells-induced inflammation is inhibited by A20 through interactions with TAX1BP1 (Tax1-binding protein 1) and A20-binding inhibitor of NF-?? activation (ABIN)-1 (A20 binding and inhibitor of NF-??) and upon phosphorylation by inhibitor of nuclear factor kappa-? kinase subunit beta (IKK?), which stabilizes it. We hypothesized that dysregulation of A20 is an important factor in uncontrolled inflammation in pediatric IBD. Patients and methods:Gene expression of A20, IKK?, ABIN-1, TAX1BP1, A20 protein, cytokine levels, and A20 phosphorylation was analyzed in the terminal ileum (TI) of 39 patients (14 non-IBD, 15 CD, and 10 UC). A20 expression and protein in T-84 cells and ex vivo biopsies of patients were measured after treatment with Escherichia coli strains or tumor necrosis factor (TNF)-?. Results:TNF-? levels and A20 expression were increased in the TI of CD patients. A20 protein levels and ABIN-1 expression were low, TAX1BP1 expression was high, and IKK? was unchanged. A20 expression positively correlated with biopsy TNF-? levels and inflammatory markers in CD patients. A20 phosphorylation appeared lower in CD patients. A20 expression in TI biopsies from CD patients and T84 cells was triggered with E. coli, strain LF82, while A20 protein levels remained unchanged. Conclusion:We describe a potential mechanism related to failure of A20 to suppress inflammation in CD, characterized by high A20 expression and low A20 protein levels. The dysregulation of A20 is potentially due to alterations in ABIN-1, and infection with E. coli strain LF82 could affect the function and stability of A20. Our study signifies an important finding in A20 regulation in IBD, which prevents it from suppressing inflammation.

Dataset Information

ATG16L1: A multifunctional susceptibility factor in Crohn disease.

Publications

ATG16L1: A multifunctional susceptibility factor in Crohn disease.

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