打开APP

Nature:克罗恩氏病的遗传原因

  1. 克罗恩氏病
  2. 遗传原因

来源:Nature中文网 2014-02-28 21:32

自噬基因ATG16L1中的Thr 300-to-Ala (T300A)多态性已被发现是克罗恩氏病(一种慢性肠道炎症,目前正成为工业化国家一个较大的健康问题)的一个显著的易感因子。

自噬基因ATG16L1中的Thr 300-to-Ala (T300A)多态性已被发现是克罗恩氏病(一种慢性肠道炎症,目前正成为工业化国家一个较大的健康问题)的一个显著的易感因子。

这项研究显示,Thr 300位于人ATG16L内一个“半胱天冬酶解理点”的P1′位置,在那里它能提高ATG16L1对由“半胱天冬酶-3”介导的解理的敏感性。这会降低对响应于代谢应激或死亡受体刺激而发生的自噬作用的诱导,导致炎性细胞因子分泌的增加。

这些发现提出这样一个可能性:“半胱天冬酶-3”激活通道的治疗性抑制也许能恢复自噬作用和肠道动态平衡——部分是通过稳定ATG16L1来发挥这种作用。(生物谷Bioon.com)

生物谷推荐的英文摘要

Nature               doi:10.1038/nature13044

A Crohn’s disease variant in Atg16l1 enhances its degradation by caspase 3

Aditya Murthy,  Yun Li,  Ivan Peng,  Mike Reichelt,  Anand Kumar Katakam,  Rajkumar Noubade,  Merone Roose-Girma,  Jason DeVoss,  Lauri Diehl,  Robert R. Graham  & Menno van Lookeren Campagne

Crohn’s disease is a debilitating inflammatory bowel disease (IBD) that can involve the entire digestive tract. A single-nucleotide polymorphism (SNP) encoding a missense variant in the autophagy gene ATG16L1 (rs2241880, Thr300Ala) is strongly associated with the incidence of Crohn’s disease. Numerous studies have demonstrated the effect of ATG16L1 deletion or deficiency; however, the molecular consequences of the Thr300Ala (T300A) variant remains unknown. Here we show that amino acids 296–299 constitute a caspase cleavage motif in ATG16L1 and that the T300A variant (T316A in mice) significantly increases ATG16L1 sensitization to caspase-3-mediated processing. We observed that death-receptor activation or starvation-induced metabolic stress in human and murine macrophages increased degradation of the T300A or T316A variants of ATG16L1, respectively, resulting in diminished autophagy. Knock-in mice harbouring the T316A variant showed defective clearance of the ileal pathogen Yersinia enterocolitica and an elevated inflammatory cytokine response. In turn, deletion of the caspase-3-encoding gene, Casp3, or elimination of the caspase cleavage site by site-directed mutagenesis rescued starvation-induced autophagy and pathogen clearance, respectively. These findings demonstrate that caspase 3 activation in the presence of a common risk allele leads to accelerated degradation of ATG16L1, placing cellular stress, apoptotic stimuli and impaired autophagy in a unified pathway that predisposes to Crohn’s disease.

版权声明 本网站所有注明“来源:生物谷”或“来源:bioon”的文字、图片和音视频资料,版权均属于生物谷网站所有。非经授权,任何媒体、网站或个人不得转载,否则将追究法律责任。取得书面授权转载时,须注明“来源:生物谷”。其它来源的文章系转载文章,本网所有转载文章系出于传递更多信息之目的,转载内容不代表本站立场。不希望被转载的媒体或个人可与我们联系,我们将立即进行删除处理。

87%用户都在用生物谷APP 随时阅读、评论、分享交流 请扫描二维码下载->