LRRC19 Promotes Permeability of the Gut Epithelial Barrier Through Degrading PKC-ζ and PKCι/λ to Reduce Expression of ZO1, ZO3, and Occludin
LRRC19 Promotes Permeability of the Gut Epithelial Barrier Through Degrading PKC-ζ and PKCι/λ to Reduce Expression of ZO1, ZO3, and Occludin
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LRRC19 通过降解 PKC-γ 和 PKCγ/δ 来减少 ZO1、ZO3 和 Occludin 的表达，从而促进肠道上皮屏障的通透性
DOI：
10.1093/ibd/izaa354
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发表时间：
2021
影响因子：
4.9
通讯作者：
Rongcun Yang
中科院分区：
文献类型：
--
作者：
Xiaomin Su;Jianmei Wei;Houbao Qi;Mengli Jin;Qianjing Zhang;Yuan Zhang;Chunze Zhang;Rongcun Yang
背景功能失调的肠道上皮屏障会导致内毒素、管腔抗原和细菌更多地渗透到血液中，从而引起疾病。肠上皮屏障完整性的维持可能受到多种因素的调节。在此，我们分析了富含亮氨酸重复序列的蛋白19（LRRC19）在调节肠上皮屏障通透性中的作用。方法我们利用Lrrc19敲除（KO）小鼠和临床样本，通过透射电子、肠道通透性测定、Western印迹和免疫荧光染色来表征LRRC19在肠上皮屏障通透性中的作用。结果我们发现在肠上皮细胞中表达的LRRC19损害肠道屏障功能。透射电子显微照片显示 LRRC19KO 小鼠结肠上皮细胞的连接更紧密，间隙更窄。 LRRC19KO小鼠灌胃后血清脂多糖和4 kDa异硫氰酸荧光素-右旋糖酐水平低于野生型小鼠。我们发现LRRC19可以降低结肠上皮细胞中闭合小带（ZO）-1、ZO-3和occludin的表达。 ZO-1、ZO-3 和 occludin 表达的降低依赖于 LRRC19 通过 K48 泛素化来降解蛋白激酶 C (PKC) ζ 和 PKCι/λ。 LRRC19在人结直肠癌中的表达也与ZO-1、ZO-3、occludin、PKCζ、PKCι/λ呈负相关。 结论 LRRC19蛋白可通过降解PKC z、PKCι/λ来促进肠上皮屏障的通透性，从而减少ZO-1、ZO-3、occludin的表达。
BackgroundA dysfunctional gut epithelial barrier allows the augmented permeation of endotoxins, luminal antigens, and bacteria into the bloodstream, causing disease. The maintenance of gut epithelial barrier integrity may be regulated by multiple factors. Herein we analyze the role of leucine-rich repeat-containing protein 19 (LRRC19) in regulating the permeability of the gut epithelial barrier.MethodsWe utilizedLrrc19knockout (KO) mice and clinical samples through transmission electron, intestinal permeability assay, Western blot, and immunofluorescence staining to characterize the role of LRRC19 in the permeability of the gut epithelial barrier.ResultsWe found that LRRC19, which is expressed in gut epithelial cells, impairs gut barrier function. Transmission electron micrographs revealed a tighter junction and narrower gaps in the colon epithelium cells inLRRC19KO mice. There were lower levels of serum lipopolysaccharide and 4 kDa-fluorescein isothiocyanate-dextran after gavage inLRRC19KO mice than in wild-type mice. We found that LRRC19 could reduce the expression of zonula occludens (ZO)-1, ZO-3, and occludin in the colonic epithelial cells. The decreased expression of ZO-1, ZO-3, and occludin was dependent on degrading protein kinase C (PKC) ζ and PKCι/λ through K48 ubiquitination by LRRC19. The expression of LRRC19 was also negatively correlated with ZO-1, ZO-3, occludin, PKCζ, and PKCι/λ in human colorectal cancers.ConclusionsThe protein LRRC19 can promote the permeability of the gut epithelial barrier through degrading PKC ζ and PKCι/λ to reduce the expression of ZO-1, ZO-3, and occludin.