Defective ATG16L1-mediated removal of IRE1α drives Crohn's disease-like ileitis.
Defective ATG16L1-mediated removal of IRE1α drives Crohn's disease-like ileitis.
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DOI：
10.1084/jem.20160791
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发表时间：
2017-02
期刊：
影响因子：
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通讯作者：
Kaser A
中科院分区：
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作者：
Tschurtschenthaler M;Adolph TE;Ashcroft JW;Niederreiter L;Bharti R;Saveljeva S;Bhattacharyya J;Flak MB;Shih DQ;Fuhler GM;Parkes M;Kohno K;Iwawaki T;Janneke van der Woude C;Harding HP;Smith AM;Peppelenbosch MP;Targan SR;Ron D;Rosenstiel P;Blumberg RS;Kaser A
Tschurtschelier等人报告了一种由IRE 1 α介导的克罗恩病样回肠炎，该回肠炎发生在脑上皮Atg 16 l1缺失的小鼠中。作者提出了一种选择性自噬过程，参与了ER应激期间IRE 1 α簇的去除。ATG 16 L1 T300 A是克罗恩病（CD）的主要风险多态性，导致自噬受损，但尚不清楚这如何导致CD。在这项研究中，我们报告了肠上皮细胞（IEC）中Atg 16 l1缺失的小鼠自发发生透壁性回肠炎，以年龄依赖性方式表型回肠CD，由内质网（ER）应激传感器IRE 1 α驱动。IRE 1 α在Atg 16 l1 ΔIEC小鼠的潘氏细胞中蓄积，而ATG 16 L1 T300 A纯合子人类在肠上皮隐窝中表现出IRE 1 α的相应增加。与IRE 1 β亚型的保护作用相反，过度活化的IRE 1 α也会在Atg 16 l1; Xbp 1 ΔIEC小鼠中导致类似的早期回肠炎，其中ER应激是通过缺失未折叠蛋白反应转录因子XBP 1诱导的。选择性自噬受体视神经磷酸酶与IRE 1 α相互作用，视神经磷酸酶缺乏会在ER应激期间放大IRE 1 α水平。此外，虽然Atg 16 l1; Xbp 1 ΔIEC小鼠中存在回肠微生物群的生态失调，正如从受损的潘氏细胞抗微生物功能预测的那样，但微生物群的这种结构改变不会引发回肠炎，而是会加重葡聚糖硫酸钠诱导的结肠炎。因此，我们得出结论，IEC中有缺陷的自噬可能通过在该部位ER应激期间IRE 1 α聚集体的清除受损而易患CD回肠炎。
Tschurtschenthaler et al. report a Crohn’s disease–like ileitis mediated by IRE1α that develops in mice with intestinal-epithelial Atg16l1 deletion when they age. The authors propose a selective autophagy process involved in the removal of IRE1α clusters during ER stress. ATG16L1T300A, a major risk polymorphism in Crohn’s disease (CD), causes impaired autophagy, but it has remained unclear how this predisposes to CD. In this study, we report that mice with Atg16l1 deletion in intestinal epithelial cells (IECs) spontaneously develop transmural ileitis phenocopying ileal CD in an age-dependent manner, driven by the endoplasmic reticulum (ER) stress sensor IRE1α. IRE1α accumulates in Paneth cells of Atg16l1ΔIEC mice, and humans homozygous for ATG16L1T300A exhibit a corresponding increase of IRE1α in intestinal epithelial crypts. In contrast to a protective role of the IRE1β isoform, hyperactivated IRE1α also drives a similar ileitis developing earlier in life in Atg16l1;Xbp1ΔIEC mice, in which ER stress is induced by deletion of the unfolded protein response transcription factor XBP1. The selective autophagy receptor optineurin interacts with IRE1α, and optineurin deficiency amplifies IRE1α levels during ER stress. Furthermore, although dysbiosis of the ileal microbiota is present in Atg16l1;Xbp1ΔIEC mice as predicted from impaired Paneth cell antimicrobial function, such structural alteration of the microbiota does not trigger ileitis but, rather, aggravates dextran sodium sulfate–induced colitis. Hence, we conclude that defective autophagy in IECs may predispose to CD ileitis via impaired clearance of IRE1α aggregates during ER stress at this site.