Epithelial Sel1L is required for the maintenance of intestinal homeostasis.
Epithelial Sel1L is required for the maintenance of intestinal homeostasis.
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上皮 Sel1L 是维持肠道稳态所必需的。
DOI：
10.1091/mbc.e15-10-0724
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发表时间：
2016-02-01
影响因子：
3.3
通讯作者：
Qi L
中科院分区：
文献类型：
--
作者：
Sun S;Lourie R;Cohen SB;Ji Y;Goodrich JK;Poole AC;Ley RE;Denkers EY;McGuckin MA;Long Q;Duhamel GE;Simpson KW;Qi L
内质网（ER）相关降解（ERAD）清除ER中错误折叠的蛋白质。上皮ERAD在潘氏细胞生物学和维持小肠内稳态中起着不可或缺的作用。这些发现暗示Sel 1 L-Hrd 1 ERAD是克罗恩病的一种新的治疗靶点。炎症性肠病（IBD）是一种无法治愈的慢性特发性疾病，严重降低生活质量。内质网（ER）相关降解（ERAD）负责清除错误折叠的蛋白质;然而，其在疾病发病机制中的作用仍在很大程度上未被探索。在这里，我们表明，表达的SEL 1 L和HRD 1，最保守的分支的哺乳动物ERAD，是显着减少回肠克罗恩病（CD）。与这一观察结果一致，患有肠细胞特异性Sel 1 L缺陷（Sel 1 L ΔIEC）的实验室小鼠发生自发性肠炎，并对刚地弓形虫诱导的回肠炎易感性增加。这与潘氏细胞的严重缺陷和活泼瘤胃球菌（一种已知与CD相关的粘液溶解细菌）的不成比例增加有关。令人惊讶的是，尽管ER应激传感器IRE 1 α和效应器CHOP在Sel 1 L ΔIEC小鼠的小肠中被激活，但它们并不是小肠中观察到的ERAD缺陷相关病变的唯一原因。因此，我们的研究指出Sel 1 L-Hrd 1 ERAD在上皮细胞生物学和CD肠道炎症发病机制中的组成性作用。
Endoplasmic reticulum (ER)–associated degradation (ERAD) clears misfolded proteins in the ER. Epithelial ERAD plays an indispensable role in Paneth cell biology and the maintenance of small intestine homeostasis. The findings implicate Sel1L-Hrd1 ERAD as a novel therapeutic target for Crohn’s disease. Inflammatory bowel disease (IBD) is an incurable chronic idiopathic disease that drastically decreases quality of life. Endoplasmic reticulum (ER)–associated degradation (ERAD) is responsible for the clearance of misfolded proteins; however, its role in disease pathogenesis remains largely unexplored. Here we show that the expression of SEL1L and HRD1, the most conserved branch of mammalian ERAD, is significantly reduced in ileal Crohn’s disease (CD). Consistent with this observation, laboratory mice with enterocyte-specific Sel1L deficiency (Sel1LΔIEC) develop spontaneous enteritis and have increased susceptibility to Toxoplasma gondii–induced ileitis. This is associated with profound defects in Paneth cells and a disproportionate increase of Ruminococcus gnavus, a mucolytic bacterium with known association with CD. Surprisingly, whereas both ER stress sensor IRE1α and effector CHOP are activated in the small intestine of Sel1LΔIEC mice, they are not solely responsible for ERAD deficiency–associated lesions seen in the small intestine. Thus our study points to a constitutive role of Sel1L-Hrd1 ERAD in epithelial cell biology and the pathogenesis of intestinal inflammation in CD.