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OTUD5 negatively regulates TAK1 activation and inflammation in podocytes MPC5 cells transfected with Flag-OTUD5 (a) or si-OTUD5 (b) were stimulated with HG/PA for 30 min. Representative western blot analysis of P-TAK1. (n = 3 independent experiments). c, d Representative western blot analysis of P-TAK1 in kidney tissues of each group. (n = 6 samples). MPC5 cells transfected with Flag-OTUD5 (e) or si-OTUD5 (f) were stimulated with HG/PA for 30 min. Representative western blot analysis of phosphorylated and total protein levels of ERK, P38, and JNK. (n = 3 independent experiments). MPC5 cells transfected with si-OTUD5 were pretreated with 10 μM Takinib (TAK1 inhibitor) for 1 h before exposure to HG/PA. g Levels of P-TAK1, P-ERK, P-P38, and P-JNK were detected by western blot. h Real-time qPCR showing mRNA levels of Il6 and Tnfα. (n = 3 independent experiments; P values were determined by one-way ANOVA with Bonferroni’s correction and data are presented as mean ± SD). i His-TAK1 was transfected into NIH/3T3 with or without Flag-OTUD5 (WT or C224A). Co-IP was performed with an anti-His antibody, followed by a western blot of TAK1 and TAB2. (n = 3 independent experiments). j MPC5 cells transfected with Flag-OTUD5 (WT or C224A) were stimulated with HG/PA for 30 min. Representative western blot analysis of phosphorylated and total protein levels of TAK1, ERK, P38, and JNK. (n = 3 independent experiments). k His-TAK1(WT or K158R) was transfected into NIH/3T3 with or without Flag-OTUD5. Co-IP was performed with an anti-His antibody, followed by a western blot of TAK1 and TAB2. (n = 3 independent experiments). l His-TAK1 (WT or K158R) and Flag-OTUD5 were transfected into MPC5 cells for 24 h and then stimulated by HG/PA for 30 min. Representative western blot analysis of phosphorylated and total protein levels of TAK1, ERK, P38, and JNK. (n = 3 independent experiments).
Source publication
Recent studies have shown the crucial role of podocyte injury in the development of diabetic kidney disease (DKD). Deubiquitinating modification of proteins is widely involved in the occurrence and development of diseases. Here, we explore the role and regulating mechanism of a deubiquitinating enzyme, OTUD5, in podocyte injury and DKD. RNA-seq ana...
Citations
... Podocytes and their foot processes constitute critical components of the renal filtration barrier, governing glomerular permeability. Podocyte injury is widely recognized as a central pathological mechanism in various kidney diseases, particularly dN and primary tubular disorders (37,38). Emerging evidence indicates that podocytes utilize lactate as an energy substrate and possess intrinsic regulatory systems to maintain lactate homeostasis. ...
... As a post-translational modification, ubiquitination/ deubiquitination critically regulates protein stability and function, and is involved in the pathophysiology of many diseases [12]. Deubiquitinases (DUBs) counterbalance ubiquitination by removing ubiquitin moieties from target proteins, thereby modulating their function and stability [13]. Ubiquitin C-terminal hydrolase (UCH) L3 (UCHL3), a member of the UCH family of DUBs, has substrates, including Forkhead box protein M1 (FOXM1), Lactate dehydrogenase A (LDHA), and TNF receptor-associated factor 2 (TRAF2), which it deubiquitinates to modulate their activity [14]. ...
Background
This study investigated the role of ubiquitin C-terminal hydrolase L3 (UCHL3) in regulating endothelial cell (EC) pyroptosis and angiogenesis in diabetic foot ulcers (DFUs), with a focus on FOXM1 and NLRP3 inflammasomes.
Methods
Differentially expressed genes in DFUs were identified using the GSE134431 dataset and cross-referenced with vascular formation-related factors from GeneCard and deubiquitinases from the UbiNet 2.0 database. A rat DFU model was used to evaluate wound healing, with or without UCHL3 overexpression and FOXM1 knockdown. Histological analysis and immunohistochemistry were employed to assess tissue morphology and the expression of CD31, eNOS, UCHL3, and FOXM1. In vitro, high glucose-induced human umbilical vein ECs (HUVECs) were transfected with UCHL3 overexpression and FOXM1 knockdown constructs. Cell viability, migration, and angiogenesis were assessed.
Results
UCHL3 expression was significantly reduced in DFU tissues. UCHL3 overexpression promoted wound healing in a rat model, while FOXM1 knockdown impaired wound healing and vascular formation. In HUVECs, UCHL3 overexpression enhanced cell viability, migration, and angiogenesis, accompanied by reduced NLRP3 and N-GSDMD levels. FOXM1 knockdown reversed these effects, but treatment with the NLRP3 inhibitor, MCC950, alleviated this damage.
Conclusion
UCHL3 enhances FOXM1 deubiquitination, inhibits NLRP3 inflammasome activation, and reduces EC pyroptosis, thereby contributing to DFU healing. UCHL3 and FOXM1 are potential therapeutic targets for DFU.
... Given the critical roles of AMPK in cellular catabolic processes, it has been postulated that the reduction of AMPK activity contributes to the development of metabolic disorders such as diabetes, obesity, and their complications. Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease, which affects almost one-third of diabetic patients worldwide [8][9][10] . Loss of glomerular function and glomerular fibrosis is the final consequence of DKD 8 . ...
AMP-activated protein kinase (AMPK) has been postulated to be crucial in regulating various renal physiology and pathophysiology processes, including energy metabolism, ion and water transport, inflammation, and hypertrophy. However, the specific roles of AMPK in the podocyte, a cell critical for maintaining glomerular filtration, have not been fully explored using genetic model animals. In this study, we generated mice lacking both AMPK α1 and α2 catalytic subunits in glomerular podocytes (pmut). Our findings revealed that, surprisingly, AMPK is dispensable for normal podocyte function. These knockout mice could live as long as their wild-type littermates without showing any pathological alterations in their glomeruli or glomerular function at two years of age. However, under type 1 diabetic conditions, the diabetic pmut mice exhibited increased lipid and collagen accumulation and an elevated expression of mesenchymal proteins in their glomeruli. They also showed more significant albuminuria compared to control diabetic mice. Under high glucose culture conditions, glomeruli isolated from pmut mice demonstrated a reduced expression of mitochondrial genes (e.g., Ndufv2) and increased leakage of mitochondrial components. Additionally, there was heightened expression of genes associated with nucleotide sensing and pro-inflammatory pathways (including mb21d2, IL-1 beta, and NF-kB). These observations suggest that while AMPK is not necessary for podocyte function in healthy kidneys, it is crucial for preventing glomerular fibrosis resulting from lipotoxicity and inflammation under diabetic conditions.
... The overexpression of OTUD5 protects podocytes. OTUD5 inhibits the inflammatory response of podocytes by deubiquitinating TAK1 and inhibiting the phosphorylation activation of TAK1, which reduces podocyte damage and delays DKD [100]. Thus, enabling podocytes to overexpress OTUD5 may be a potential therapeutic strategy to delay podocyte inflammation through the OTUD5-TAK1 axis. ...
The ubiquitin-proteasome system (UPS) is a major pathway of specific intracellular protein degradation through proteasome degradation of ubiquitin-labeled substrates. Numerous biological processes, including the cell cycle, transcription, translation, apoptosis, receptor activity, and intracellular signaling, are regulated by UPS. Alterations of the UPS, which render them more or less susceptible to degradation, are responsible for disorders of renal diseases. This review aims to summarize the mechanism of UPS in renal diseases. Besides, this review explores the relationship among UPS, autophagy, and deubiquitination in the development of renal disease. The specific molecular linkages among these systems and pathogenesis, on the other hand, are unknown and controversial. In addition, we briefly describe some anti-renal disease agents targeting UPS components. This review emphasizes UPS as a promising therapeutic modality for the treatment of kidney disease. Our work, though still basic and limited, could provide options to future potential therapeutic targets for renal diseases with a UPS underlying basis.
... For instance, BLZF1 regulates gene transcription [20], while CASC3 disrupts spliceosome function [20,36]. Other notable substrates include OTUD5 [26], which influences de-ubiquitination processes [37], and PARP10 [26], a regulator of PARylation signaling [38]. Additionally, SARDH modulates sarcosine demethylation [26], showcasing PARdU's impact on metabolic pathways. ...
Poly(ADP-ribosyl)ation (PARylation) is a dynamic protein post-translational modification (PTM) mediated by ADP-ribosyltransferases (ARTs), which regulates a plethora of essential biological processes, such as DNA repair, gene expression, and signal transduction. Among these, PAR-dependent ubiquitination (PARdU) plays a pivotal role in tagging PARylated substrates for subsequent ubiquitination and degradation events through the coordinated action of enzymes, including the E3 ligase RNF146 and the ADP-ribosyltransferase tankyrase. Notably, this pathway has emerged as a key regulator of tumorigenesis, immune modulation, and cell death. This review elucidates the molecular mechanisms of the PARdU pathway, including the RNF146–tankyrase interaction, substrate specificity, and upstream regulatory pathways. It also highlights the biological functions of PARdU in DNA damage repair, signaling pathways, and metabolic regulation, with a focus on its therapeutic potential in cancer treatment. Strategies targeting PARdU, such as tankyrase and RNF146 inhibitors, synthetic lethality approaches, and immune checkpoint regulation, offer promising avenues for precision oncology. These developments underscore the potential of PARdU as a transformative therapeutic target in combating various types of human cancer.
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