Publication in detail

J Immunol. 2017 Mar 15;198(6):2457-2467. doi: 10.4049/jimmunol.1502652. Epub 2017 Feb 15.

The Inflammatory Bowel Disease-Associated Autophagy Gene Atg16L1T300A Acts as a Dominant Negative Variant in Mice.

Gao, P; Liu, H; Huang, H; Zhang, Q; Strober, W; Zhang, F

Chinese Academy of Sciences, Beijing 100101, China. University of Chinese Academy of Sciences, Beijing 100049, China. National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.

Abstract:
The basis of the increased risk for Crohn's disease conferred by the Atg16L1T300A polymorphism is incompletely understood. An important step forward came from the recent demonstration that the murine equivalent of Atg16L1T300A (Atg16L1T316A) exhibits increased susceptibility to caspase 3-mediated cleavage and resulting decreased levels of full-length Atg16L1 in macrophages. However, although this finding showed that this polymorphism is a loss-of-function abnormality, it did not address the possibility that this polymorphism also affects the function of a normal Atg16L1 allele in heterozygous mice. Therefore, we evaluated the function of the Atg16L1T300A polymorphism heterozygote and homozygote in knock-in (KI) mice. Surprisingly, we found that macrophages from both types of KI mice exhibit defective autophagic induction; accordingly, both types of mice exhibit defects in bacterial clearance coupled with increased inflammasome cytokine (IL-1β) responses. Furthermore, macrophages from both types of KI mice displayed defects in TNF-α-induced Atg16L1T300A cleavage, increased retention of bacteria, bacterial dissemination, and Salmonella-induced colitis. These studies suggested that chromosomes bearing the Atg16L1T300A polymorphism can interfere with the function of the wild-type (WT) Atg16L1 allele and, thus, that the Crohn's disease risk polymorphism is a dominant-negative variant with the potential to act as a disease factor, even when present on only one chromosome. This conclusion was supported by the finding that mice bearing a WT Atg16L1 allele and a null allele (Atg16L1KO/+ mice) exhibit normal autophagic function equivalent to that of WT mice.

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