LRRC19 Promotes Permeability of the Gut Epithelial Barrier Through Degrading PKC-ζ and PKCι/λ to Reduce Expression of ZO1, ZO3, and Occludin

Abstract

Background A 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. Methods We utilized Lrrc19 knockout (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. Results We 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 in LRRC19 KO mice. There were lower levels of serum lipopolysaccharide and 4 kDa-fluorescein isothiocyanate-dextran after gavage in LRRC19 KO 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. Conclusions The 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.

Dietary nobiletin regulated cefuroxime- and levofloxacin-associated “gut microbiota-metabolism” imbalance and intestinal barrier dysfunction in mice

“…63 TJs play a key role in maintaining the integrity of the intestinal epithelial barrier, with occludin and ZO-1 being crucial proteins associated with intestinal permeability and the mucosal barrier function. 64,65 Importantly, we demonstrated that dietary NOB effectively ameliorated CFX- and LVX-associated intestinal barrier injury by significantly upregulating ZO-1 expression. These results were consistent with previous studies, which showed that NOB enhanced the intestinal barrier function by upregulating occludin and ZO-1 expressions in models of intestinal inflammation.…”

Chlorogenic acid alleviates the intestinal barrier dysfunction and intestinal flora disorder induced by cisplatin

“…Dysfunction in this barrier is a pivotal factor contributing to increased intestinal mucosal permeability, thereby mediating the onset and progression of ulcerative colitis [21] . Two tight junctions composed of ZO and Occludin proteins [22][23][24] form the basis of the integrity of tight junctions. Occludin has the functions of sealing cell space, regulating paracellular transport and regulating signal conduction [25] , etc., while ZO-1 affects cell proliferation, differentiation and growth, and regulates intercellular signal transduction and penetration [26] .…”

Downregulation of LRRC19 Is Associated with Poor Prognosis in Colorectal Cancer

“…e latest research demonstrated that LRRC19 can increase the permeability of the gut epithelial barrier by degrading PKC to reduce the expression of ZO-1, ZO-3, and occludin [35].…”

“…LRRC19 was also mentioned for its therapeutic potential in pressure ulcers, by promoting NF-kB-dependent pro-inflammatory response [ 34 ]. The latest research demonstrated that LRRC19 can increase the permeability of the gut epithelial barrier by degrading PKC to reduce the expression of ZO-1, ZO-3, and occludin [ 35 ].…”