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Resveratrol reduces COMPopathy in mice through activation of autophagy
bioRxiv - Pathology Pub Date : 2020-10-27 , DOI: 10.1101/2020.10.26.355628
Jacqueline T. Hecht , Francoise Coustry , Alka C. Veerisetty , Mohammad G. Hossain , Karen L. Posey

Misfolding mutations in cartilage oligomeric matrix protein (COMP) cause it to be retained within in ER of chondrocytes, stimulating a multitude of damaging cellular responses including ER stress, inflammation and oxidative stress which ultimately culminates in the death of growth plate chondrocytes and pseudoachondroplasia (PSACH). Previously, we demonstrated that an antioxidant, resveratrol, substantially reduces the intracellular accumulation of mutant COMP, dampens cellular stress and lowers the level of growth plate chondrocyte death. In addition, we showed that resveratrol reduces mTORC1 (mammalian target of rapamycin complex 1) signaling, suggesting a potential mechanism. In this work, we investigate the role of autophagy in treatment of COMPopathies. In cultured chondrocytes expressing wild type or mutant COMP (MT-COMP), resveratrol significantly increased the number of large LC3 vesicles, directly demonstrating that resveratrol stimulated autophagy is an important component of the resveratrol-driven mechanism responsible for the degradation of mutant COMP. Moreover, pharmacological inhibitors of autophagy suppressed degradation of MT-COMP in our established mouse model of PSACH. In contrast, blockage of the proteasome did not substantially alter resveratrol clearance of mutant COMP from growth plate chondrocytes. Mechanistically, resveratrol increased SIRT1 and PP2A expression and reduced MID1 expression and activation of pAKT and mTORC1 signaling in growth plate chondrocytes, allowing clearance of mutant COMP by autophagy. Importantly, we show that optimal reduction in growth plate pathology, including decreased mutant COMP retention, decreased mTORC1 signaling and restoration of chondrocyte proliferation was attained when treatment was initiated between birth to one week of age in MT-COMP mice, translating to birth to approximately 2 years of age in PSACH children. These results clearly demonstrate that resveratrol stimulates clearance of mutant COMP by an autophagy-centric mechanism. Key Words: pseudoachondroplasia, autophagy, resveratrol, dwarfism, cartilage oligomeric matrix protein (COMP), proteasome, mTORC1

中文翻译:

白藜芦醇通过激活自噬减少小鼠COMP病变

软骨寡聚基质蛋白(COMP)的错误折叠突变使它保留在软骨细胞的ER中,刺激了许多有害的细胞反应,包括ER应激,炎症和氧化应激,最终导致生长板软骨细胞和假软骨发育不良(PSACH)的死亡。 )。以前,我们证明了一种抗氧化剂白藜芦醇可大大减少突变体COMP的细胞内积累,减轻细胞压力并降低生长板软骨细胞死亡的水平。此外,我们显示白藜芦醇可降低mTORC1(雷帕霉素复合物1的哺乳动物靶标)信号传导,提示其潜在机制。在这项工作中,我们调查了自噬在治疗交感神经中的作用。在表达野生型或突变型COMP(MT-COMP)的培养软骨细胞中,白藜芦醇显着增加了大型LC3囊泡的数量,直接表明白藜芦醇刺激的自噬是白藜芦醇驱动的机制的重要组成部分,该机制负责突变体COMP的降解。此外,在我们已建立的PSACH小鼠模型中,自噬的药理抑制剂抑制了MT-COMP的降解。相反,蛋白酶体的阻滞基本上不改变突变体COMP从生长板软骨细胞中的白藜芦醇清除率。从机制上讲,白藜芦醇增加了生长板软骨细胞中SIRT1和PP2A的表达并降低了MID1的表达以及pAKT和mTORC1信号的激活,从而允许通过自噬清除突变体COMP。重要的是,我们显示出生长板病理学的最佳减少,包括突变体COMP保留的减少,在MT-COMP小鼠出生至1周龄之间开始治疗时,可降低mTORC1信号传导并恢复软骨细胞增殖,而PSACH儿童则可在出生至2岁左右时开始治疗。这些结果清楚地证明白藜芦醇通过以自噬为中心的机制刺激突变体COMP的清除。关键词:假软骨发育不良,自噬,白藜芦醇,侏儒症,软骨寡聚基质蛋白(COMP),蛋白酶体,mTORC1
更新日期:2020-10-30
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