Life sciences · 2026
USP24 inhibits autophagy in diabetic myocardial disorder by regulating TRAF6-mediated ubiquitination of Beclin-1.
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Wu Shenglin, Zhou Yueran, Shu Mengjuan, Zhang Hongwei, Situ Qiwei, Bao Zhijun, Hu Zuoqi, Zhu Jinxiu
Аннотация
AIMS: Although autophagy inhibition is implicated in the onset and progression of diabetic myocardial disorder (DMD), its molecular mechanisms remain poorly understood. Herein, we assessed the regulatory role of the USP24-TRAF6-Beclin-1 pathway in autophagy and its potential therapeutic value in DMD.
MATERIALS AND METHODS: A diabetic mouse model was established using a high-fat diet combined with streptozotocin injection. Primary neonatal mouse cardiomyocytes and H9c2 cells were cultured in vitro under high-glucose and palmitate conditions to mimic DMD. Autophagic flux was assessed by transmission electron microscopy, the mRFP-GFP-LC3 reporter assay, and Western blot analysis of LC3, p62, and Beclin-1. Molecular mechanisms were explored using Co-immunoprecipitation, Western blotting, lentiviral-mediated knockdown or overexpression, and Cell Counting Kit-8 assays.
KEY FINDINGS: USP24 and TRAF6 were upregulated in DMD both in vivo and in vitro, accompanied by decreased Beclin-1, an elevated LC3-II/LC3-I ratio, increased p62, and impaired autophagolysosomal formation. USP24 directly interacted with and deubiquitinated TRAF6, thereby stabilizing its protein. TRAF6 bound to and ubiquitinated Beclin-1, promoting its degradation. Silencing USP24 reduced TRAF6, restored Beclin-1, enhanced autophagic flux, increased Bcl-2, and improved cardiomyocyte viability in DMD. Overexpression of TRAF6 reversed the effects induced by USP24 knockdown.
SIGNIFICANCE: USP24 inhibits autophagy in DMD, specifically by deubiquitinating TRAF6 and stabilizing its expression, while TRAF6 promotes Beclin-1 ubiquitination and degradation. Targeting the USP24 may offer a novel therapeutic strategy for DMD.
MATERIALS AND METHODS: A diabetic mouse model was established using a high-fat diet combined with streptozotocin injection. Primary neonatal mouse cardiomyocytes and H9c2 cells were cultured in vitro under high-glucose and palmitate conditions to mimic DMD. Autophagic flux was assessed by transmission electron microscopy, the mRFP-GFP-LC3 reporter assay, and Western blot analysis of LC3, p62, and Beclin-1. Molecular mechanisms were explored using Co-immunoprecipitation, Western blotting, lentiviral-mediated knockdown or overexpression, and Cell Counting Kit-8 assays.
KEY FINDINGS: USP24 and TRAF6 were upregulated in DMD both in vivo and in vitro, accompanied by decreased Beclin-1, an elevated LC3-II/LC3-I ratio, increased p62, and impaired autophagolysosomal formation. USP24 directly interacted with and deubiquitinated TRAF6, thereby stabilizing its protein. TRAF6 bound to and ubiquitinated Beclin-1, promoting its degradation. Silencing USP24 reduced TRAF6, restored Beclin-1, enhanced autophagic flux, increased Bcl-2, and improved cardiomyocyte viability in DMD. Overexpression of TRAF6 reversed the effects induced by USP24 knockdown.
SIGNIFICANCE: USP24 inhibits autophagy in DMD, specifically by deubiquitinating TRAF6 and stabilizing its expression, while TRAF6 promotes Beclin-1 ubiquitination and degradation. Targeting the USP24 may offer a novel therapeutic strategy for DMD.