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Published on: September 1, 2015
Targeting TRAF6 inhibits cystogenesis in autosomal dominant polycystic kidney disease
Ying Ren1, Yaoyao Pan1, Xiaodan Zhu2
1Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004 Jiangsu, China.
Abstract:
Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney disorder, characterized by the progressive formation of multiple cysts in the kidneys. Post-translational modifications (PTMs) are increasingly recognized as key players in cyst formation. However, the role of ubiquitination, one of the most significant PTMs, in regulating cystogenesis in ADPKD remains largely unexplored. Here, we identified that TRAF6, an E3 ubiquitin ligase, was significantly upregulated in ADPKD cells, mouse models, and patient tissues. TRAF6 interacted with the transcription factor STAT3, enhancing its activation and transcriptional activity by selectively increasing K63-linked ubiquitination, thereby contributing to renal cyst growth in both ADPKD cells and mice. Furthermore, the inhibition of TRAF6 significantly suppressed STAT3 transcriptional activity and slowed cyst growth in both in vitro and in vivo models. Therefore, targeting TRAF6 may represent a novel therapeutic strategy for ADPKD treatment.
Insights
TRAF6, an E3 ubiquitin ligase, drives kidney cyst growth in autosomal dominant polycystic kidney disease (ADPKD) by activating STAT3. Inhibiting TRAF6 shows promise for treating ADPKD.
Area of Science:
- Biochemistry
- Genetics
- Nephrology
Background:
- Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic kidney disorder.
- Cyst formation in ADPKD involves post-translational modifications (PTMs).
- The role of ubiquitination in ADPKD cystogenesis is not well understood.
Purpose of the Study:
- To investigate the role of ubiquitination, specifically TRAF6, in ADPKD.
- To explore the mechanism by which TRAF6 influences renal cyst growth.
- To evaluate TRAF6 as a potential therapeutic target for ADPKD.
Main Methods:
- Identified TRAF6 upregulation in ADPKD cells, mouse models, and patient tissues.
- Investigated the interaction between TRAF6 and STAT3.
- Assessed the effect of TRAF6 inhibition on STAT3 activity and cyst growth in vitro and in vivo.
Main Results:
- TRAF6 was significantly upregulated in ADPKD.
- TRAF6 enhanced STAT3 activation and transcriptional activity via K63-linked ubiquitination.
- TRAF6 inhibition suppressed STAT3 activity and slowed renal cyst growth.
Conclusions:
- TRAF6 plays a crucial role in ADPKD cystogenesis by regulating STAT3.
- Targeting TRAF6 offers a potential novel therapeutic strategy for ADPKD.
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