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Published on: November 10, 2021
OTUD7B attenuates renal fibrosis by regulating PRDX1 protein stability
Yufeng Xiong1, Xiaojie Zhao2, Xuke Qin3
1Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China; Institute of Urologic Disease, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China.
Introduction:
Renal fibrosis as a common pathological endpoint in chronic kidney disease (CKD) and end-stage renal disease (ESRD) is a serious threat to patients' life and health. In recent years, the link between epigenetic modifications and renal fibrosis has been increasingly discovered.
Objectives:
This study aimed to investigate the effects of the deubiquitinating enzyme OTUD7B on renal fibrosis and its underlying mechanism.
Methods:
Transcriptome sequencing of control and fibrotic cells were performed to screen for deubiquitinating enzymes, and the expression of these enzymes were validated in cellular models, animal models, and clinical specimens. The specific role of OTUD7B in renal fibrosis was elucidated through knockdown and overexpression experiments. Subsequently, IP-MS was employed to identify OTUD7B downstream targets, confirming its interaction with PRDX1 and detecting PRDX1 ubiquitination levels and sites. Finally, IP and UbiBrowser were used to predicte SMURF1 as the PRDX1 ubiquitin ligase. Detection of ubiquitination levels and sites revealed that OTUD7B and SMURF1 maintained PRDX1 protein stability together.
Results:
The reduction of renal fibrosis deubiquitinating enzyme, OTUD7B, was identified by RNA sequencing and validated in cellular, animal and human samples. In addition, its function was verified by knockdown and overexpression of OTUD7B, with overexpression attenuating renal fibrosis and knockdown exacerbating it. Mechanistically, through reducing SMURF1-mediated K63-linked ubiquitination and subsequent lysosomal degradation of PRDX1, OTUD7B elevated PRDX1 expression, resulting in attenuation of renal fibrosis.
Conclusion:
Collectively, targeting the OTUD7B-SMURF1-PRDX1 axis may offer a promising therapeutic approach for renal fibrosis.
Insights
The deubiquitinating enzyme OTUD7B protects against renal fibrosis by stabilizing PRDX1. Targeting the OTUD7B-SMURF1-PRDX1 pathway offers a new therapeutic strategy for kidney fibrosis.
Area of Science:
- Nephrology
- Epigenetics
- Molecular Biology
Background:
- Renal fibrosis is a common endpoint for chronic kidney disease (CKD) and end-stage renal disease (ESRD).
- Epigenetic modifications are increasingly recognized for their role in renal fibrosis development.
- Understanding the molecular mechanisms underlying renal fibrosis is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the role of the deubiquitinating enzyme OTUD7B in renal fibrosis.
- To elucidate the underlying molecular mechanisms by which OTUD7B influences renal fibrosis.
- To identify potential therapeutic targets for renal fibrosis based on OTUD7B's function.
Main Methods:
- Transcriptome sequencing to identify key deubiquitinating enzymes in fibrosis.
- Validation of OTUD7B expression in cellular, animal, and human kidney samples.
- Knockdown and overexpression studies to determine OTUD7B's functional role in renal fibrosis.
- Co-immunoprecipitation and mass spectrometry (IP-MS) to identify OTUD7B interacting partners.
- Ubiquitination assays to analyze PRDX1 modification and stability.
Main Results:
- OTUD7B expression was reduced in renal fibrosis and validated across multiple models.
- Overexpression of OTUD7B attenuated renal fibrosis, while knockdown exacerbated it.
- OTUD7B was found to interact with PRDX1 and reduce its ubiquitination mediated by SMURF1.
- This mechanism led to increased PRDX1 protein stability and expression, ultimately mitigating renal fibrosis.
Conclusions:
- OTUD7B plays a protective role against renal fibrosis.
- The OTUD7B-SMURF1-PRDX1 axis is a key pathway regulating renal fibrosis.
- Targeting this axis presents a promising therapeutic strategy for treating renal fibrosis.
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