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Leptospira interrogansinduces the degradation of E-cadherin scaffolding proteins p0071 and p120-catenin to disrupt the junctional complex

ABSTRACT: Leptospira interrogans disseminates hematogenously to reach the target organs by disrupting the epithelial junctional complexes (JCs). We have previously demonstrated that transmigration of L. interrogansacross polarized renal proximal tubule epithelial cells (RPTECs) induces E-cadherin (E-cad) endocytosis, mislocalization of JC proteins and cytoskeletal rearrangement without significant changes in the transcript levels of JC-associated proteins. Here, we use a combination of proteomic and imaging analysis with chemical inhibition studies to demonstrate that L. interrogansco-opts host protein degradation pathways to target scaffolding proteins, p0071 and p120-catenin, which stabilize E-cad at the plasma membrane. L. interrogans-induced decrease of RPTECs transepithelial electrical resistance can be totally mitigated by the proteasomal inhibitors MG-132 or bortezomib, or partially prevented by the pan-caspase inhibitor Z-VAD-FMK. Furthermore, the combination of MG-132 with the lysosomal inhibitor bafilomycin significantly prevent p120-catenin degradation and its displacement from the JC without preventing p0071 proteolysis. The degradation and displacement of p0071 from the JC was inhibited by Z-VAD-FMK. These results demonstrate that p120-catenin and p0071 have redundant roles as proteins stabilizing E-cad at the JC of RPTECs. L. interrogans induces the degradation of both proteins by multiple pathways to efficiently destroy the monolayer integrity.

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Claudia Toma

PROVIDER: PXD040838 | JPOST Repository | Thu Aug 31 00:00:00 BST 2023

REPOSITORIES: jPOST

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Project description:The purpose of this study is to identify genetic predictors of ACE inhibitor-associated angioedema. In addition to preventing the formation of the pressor angiotensin II, ACE inhibitors prevent the carboxyl-terminal degradation of the vasoactive substances bradykinin and substance P. Angioedema is hypothesized to result from defective amino-terminal degradation of bradykinin or substance P in patients in whom ACE is inhibited. For example, activity of dipeptidyl peptidase IV (DPP-IV), the enzyme responsible for the inactivation of substance P when ACE is inhibited, is decreased in patients with angioedema. In preliminary studies, we have identified SNPs in the DPP4 gene that associate with DPP-IV activity and, in blacks, with risk of angioedema. This project will use genome-wide genotyping to compare 250 cases and 568 ACE inhibitor-exposed control subjects (131 cases and 288 controls ascertained at Vanderbilt and 70 cases and 280 controls ascertained at the Marshfield Clinic). We plan a 2-stage analysis of associations between SNPs and angioedema - first, we will study DPP4 SNPs for association with angioedema and, second, we will explore associations using the full GWAS data set. Depending on the platform, additional DPP4 SNPs will be used to fully tag common genetic variants in both African American and European American samples. Based on the HapMap data, there are 14 tagging SNPs in people of European descent and 34 in Yoruba (selection criteria MAF>0.05 and r2>0.8). Cases were defined as having ACE inhibitor-associated angioedema if they had had swelling of the lips, throat, tongue or face while taking an ACE inhibitor but had never had angioedema while not taking an ACE inhibitor. For simplicity, intestinal edema was excluded. Control subjects were treated for at least 6 months with an ACE inhibitor without angioedema. Because black Americans are known to be overrepresented among patients with ACE inhibitor-associated angioedema, control subjects were prespecified to be 50% black American, 50% white American, and 50% female. At Vanderbilt, the medical history, including the history of angioedema, was confirmed by a research nurse or physician using a detailed case report form. Characteristics of Vanderbilt cases appear in the Table. At Marshfield, medical history will be confirmed by chart review. The Marshfield cohort is 98% white American and 57% female with a mean age of 47.2 years.

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Leptospira interrogansinduces the degradation of E-cadherin scaffolding proteins p0071 and p120-catenin to disrupt the junctional complex

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