The Inflammatory Bowel Disease-Associated Autophagy Gene Atg16L1T300A Acts as a Dominant Negative Variant in Mice----中国科学院微生物研究所

科研成果

论文题目:	The Inflammatory Bowel Disease-Associated Autophagy Gene Atg16L1T300A Acts as a Dominant Negative Variant in Mice
作者:	Gao Ping, Liu Hongtao, Huang Huarong, Zhang Qi, Strober Warren, and Zhang Fuping*.
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刊物名称:	J Immunol
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年份:	2017
影响因子:	5.287
论文下载:	http://www.jimmunol.org/content/early/2017/02/15/jimmunol.1502652
摘要:	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-1beta) responses. Furthermore, macrophages from both types of KI mice displayed defects in TNF-alpha-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.