The cerebral cavernous malformation disease causing gene KRIT1 participates in intestinal epithelial barrier maintenance and regulation
The cerebral cavernous malformation disease causing gene KRIT1 participates in intestinal epithelial barrier maintenance and regulation
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DOI：
10.1096/fj.201800343r
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发表时间：
2018-09
期刊：
影响因子：
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通讯作者：
Yitang Wang;Ye Li;Jinjing Zou;S. Polster;R. Lightle;Thomas Moore;M. Dimaano;T. He;C. Weber;I. Awad;Le Shen
中科院分区：
文献类型：
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作者：
Yitang Wang;Ye Li;Jinjing Zou;S. Polster;R. Lightle;Thomas Moore;M. Dimaano;T. He;C. Weber;I. Awad;Le Shen
上皮屏障的维持和调节需要细胞-细胞连接下方完整的连接周围肌动球蛋白环。通过寻找影响肌动蛋白细胞骨架的已知因素，我们发现 Krev 相互作用捕获蛋白 1 (KRIT1) 通过多种机制作为上皮屏障功能的主要调节因子。 KRIT1 在小肠和结肠上皮中表达，分化的 Caco-2 肠上皮中的 KRIT1 敲低会降低上皮屏障功能并增加阳离子选择性。 KRIT1 敲低通过限制小分子和大分子通透性消除了 Rho 相关蛋白激酶诱导和肌球蛋白 II 运动抑制剂诱导的屏障丧失，但不影响肌球蛋白轻链激酶诱导的上皮屏障功能增加。这些数据表明 KRIT1 参与 Rho 相关蛋白激酶和肌球蛋白 II 运动依赖性（但不是肌球蛋白轻链激酶依赖性）上皮屏障调节。 KRIT1 敲除加剧了低剂量 TNF 诱导的屏障丧失，同时增加了裂解的 casρase-3 的产生。这两个事件都被泛半胱天冬酶抑制所阻断，表明 KRIT1 通过限制上皮细胞凋亡来调节 TNF 诱导的屏障丧失。这些数据表明，KRIT1通过多种途径控制上皮屏障的维持和调节，表明脑海绵状血管瘤疾病中的KRIT1突变可能会改变上皮功能并影响人类健康。-Wang, Y., Li, Y., Zou, J., Polster, S. P., Lightle, R., Moore, T., Dimaano, M., He, T.-C., Weber, C. R., Awad, I. A.，Shen，L.脑海绵状血管瘤疾病致病基因KRIT1参与肠上皮屏障的维持和调节。 FASEB J. 33, 2132–2143 (2019)。 www.fasebj.org
Epithelial barrier maintenance and regulation requires an intact perijunctional actomyosin ring underneath the cell‐cell junctions. By searching for known factors affecting the actin cytoskeleton, we identified Krev interaction trapped protein 1 (KRIT1) as a major regulator for epithelial barrier function through multiple mechanisms. KRIT1 is expressed in both small intestinal and colonic epithelium, and KRIT1 knockdown in differentiated Caco‐2 intestinal epithelium decreases epithelial barrier function and increases cation selectivity. KRIT1 knockdown abolished Rho‐associated protein kinase‐induced and myosin II motor inhibitor–induced barrier loss by limiting both small and large molecule permeability but did not affect myosin light chain kinase–induced increases in epithelial barrier function. These data suggest that KRIT1 participates in Rho‐associated protein kinase‐ and myosin II motor–dependent (but not myosin light chain kinase–dependent) epithelial barrier regulation. KRIT1 knockdown exacerbated low‐dose TNF‐induced barrier loss, along with increased cleaved casρase‐3 production. Both events are blocked by pan‐caspase inhibition, indicating that KRIT1 regulates TNF‐induced barrier loss through limiting epithelial apoptosis. These data indicate that KRIT1 controls epithelial barrier maintenance and regulation through multiple pathways, suggesting that KRIT1 mutation in cerebral cavernous malformation disease may alter epithelial function and affect human health.—Wang, Y., Li, Y., Zou, J., Polster, S. P., Lightle, R., Moore, T., Dimaano, M., He, T.‐C., Weber, C. R., Awad, I. A., Shen, L. The cerebral cavernous malformation disease causing gene KRITl participates in intestinal epithelial barrier maintenance and regulation. FASEB J. 33, 2132–2143 (2019). www.fasebj.org