USP36-Mediated Deubiquitination of DOCK4 Contributes to the Diabetic Renal Tubular Epithelial Cell Injury via Wnt/β-Catenin Signaling Pathway

Suwei Zhu,Zhengguo Cui,Wei Sheng,Hong Feng,Tianyi Dong,Shaoshuai Hou,Yao Lu,Qiang Wan

doi:10.3389/fcell.2021.638477

Abstract

Diabetic kidney disease (DKD) has become the leading cause of end-stage renal disease but the efficacy of current treatment remains unsatisfactory. The pathogenesis of DKD needs a more in-depth research. Ubiquitin specific proteases 36 (USP36), a member of deubiquitinating enzymes family, has aroused wide concerns for its role in deubiquitinating and stabilizing target proteins. Nevertheless, the role of USP36 in diabetes has never been reported yet. Herein, we identified an increased expression of USP36 both in vitro and in vivo in diabetic renal tubular epithelial cells (TECs), and its overexpression is related to the enhanced epithelial-to-mesenchymal transition (EMT). Further investigation into the mechanisms proved that USP36 could directly bind to and mediate the deubiquitination of dedicator of cytokinesis 4 (DOCK4), a guanine nucleotide exchange factor (GEF) that could activate Wnt/β-catenin signaling pathway and induce EMT. Our study revealed a new mechanism that USP36 participates in the pathogenesis of DKD, and provided potential intervening targets accordingly.

Highlights

Along with the worldwide prevalence of diabetes, the incidence of its major microvascular complication diabetic kidney disease (DKD) increased rapidly, and currently DKD has become the leading cause of end-stage renal disease (ESRD) (Li et al, 2017)
These results indicated that Ubiquitin specific proteases 36 (USP36) was upregulated in DKD, which suggested that USP36 may be involved in the pathogenesis and development of DKD
The results revealed that dedicator of cytokinesis 4 (DOCK4) knockdown effectively abolished USP36 overexpressioninduced epithelial-to-mesenchymal transition (EMT) through suppressing Wnt/β-catenin signaling pathway in tubular epithelial cells (TECs) (Figures 5M,N)

Summary

Introduction

Along with the worldwide prevalence of diabetes, the incidence of its major microvascular complication diabetic kidney disease (DKD) increased rapidly, and currently DKD has become the leading cause of end-stage renal disease (ESRD) (Li et al, 2017). Along with the recognition of the roles USP playing in modulating cell cycle progression, gene expression, cell survival and apoptosis, UPS emerged as one crucial modulator for cellular morphological and functional homeostasis (MeyerSchwesinger, 2019). Accumulating data suggested that UPS serves as an active participant in the pathogenesis of several lines of kidney pathologies, such as glomerulonephritis (Bontscho et al, 2011), acute kidney injuries (Palombella et al, 1994) and renal fibrosis (Fukasawa, 2012). A study reported that UPS was enhanced in DKD and high glucose stimulation might promote proteasomal activities (Aghdam et al, 2013), while another report suggested that proteasomal activities were reduced in DKD (Portero-Otín et al, 1999). The concrete role of UPS in DKD still remains exploration

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