IRF1-mediated upregulation of PARP12 promotes cartilage degradation by inhibiting PINK1/Parkin dependent mitophagy through ISG15 attenuating ubiquitylation and SUMOylation of MFN1/2.

IF 14.3 1区 医学 Q1 CELL & TISSUE ENGINEERING Bone Research Pub Date : 2024-10-28 DOI:10.1038/s41413-024-00363-3
Zengfa Deng, Dianbo Long, Changzhao Li, Hailong Liu, Wei Li, Yanlin Zhong, Xiaolin Mo, Ruiyun Li, Zibo Yang, Yan Kang, Guping Mao
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Abstract

Osteoarthritis (OA) is an age-related cartilage-degenerating joint disease. Mitochondrial dysfunction has been reported to promote the development of OA. Poly (ADP-ribose) polymerase family member 12 (PARP12) is a key regulator of mitochondrial function, protein translation, and inflammation. However, the role of PARP12 in OA-based cartilage degradation and the underlying mechanisms are relatively unknown. Here, we first demonstrated that PARP12 inhibits mitophagy and promotes OA progression in human OA cartilage and a monosodium iodoacetate-induced rat OA model. Using mass spectrometry and co-immunoprecipitation assay, PARP12 was shown to interact with ISG15, upregulate mitofusin 1 and 2 (MFN1/2) ISGylation, which downregulated MFN1/2 ubiquitination and SUMOylation, thereby inhibiting PINK1/Parkin-dependent chondrocyte mitophagy and promoting cartilage degradation. Moreover, inflammatory cytokine-induced interferon regulatory factor 1 (IRF1) activation was required for the upregulation of PARP12 expression, and it directly bound to the PARP12 promoter to activate transcription. XAV-939 inhibited PARP12 expression and suppressed OA pathogenesis in vitro and in vivo. Clinically, PARP12 can be used to predict the severity of OA; thus, it represents a new target for the study of mitophagy and OA progression. In brief, the IRF1-mediated upregulation of PARP12 promoted cartilage degradation by inhibiting PINK1/Parkin-dependent mitophagy via ISG15-based attenuation of MFN1/2 ubiquitylation and SUMOylation. Our data provide new insights into the molecular mechanisms underlying PARP12-based regulation of mitophagy and can facilitate the development of therapeutic strategies for the treatment of OA.

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IRF1 介导的 PARP12 上调通过 ISG15 削弱 MFN1/2 的泛素化和 SUMO 化,抑制 PINK1/Parkin 依赖的有丝分裂,从而促进软骨降解。
骨关节炎(OA)是一种与年龄有关的软骨退化性关节疾病。据报道,线粒体功能障碍会促进 OA 的发展。聚(ADP-核糖)聚合酶家族成员 12(PARP12)是线粒体功能、蛋白质翻译和炎症的关键调节因子。然而,PARP12 在以 OA 为基础的软骨降解中的作用及其内在机制却相对未知。在这里,我们首次证明了 PARP12 在人类 OA 软骨和碘乙酸钠诱导的大鼠 OA 模型中抑制有丝分裂并促进 OA 进展。通过质谱分析和共免疫沉淀分析,PARP12与ISG15相互作用,上调mitofusin 1和2(MFN1/2)的ISGylation,从而下调MFN1/2的泛素化和SUMOylation,从而抑制PINK1/Parkin依赖的软骨细胞有丝分裂,促进软骨降解。此外,PARP12的表达需要炎性细胞因子诱导的干扰素调节因子1(IRF1)激活,它直接与PARP12启动子结合激活转录。XAV-939抑制了PARP12的表达,并抑制了体外和体内OA的发病机制。在临床上,PARP12可用于预测OA的严重程度;因此,它是研究有丝分裂和OA进展的一个新靶点。简而言之,IRF1介导的PARP12上调通过基于ISG15的MFN1/2泛素化和SUMO化衰减,抑制了PINK1/Parkin依赖的有丝分裂,从而促进了软骨降解。我们的数据为基于PARP12的有丝分裂调控的分子机制提供了新的见解,有助于开发治疗OA的策略。
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来源期刊
Bone Research
Bone Research CELL & TISSUE ENGINEERING-
CiteScore
20.00
自引率
4.70%
发文量
289
审稿时长
20 weeks
期刊介绍: Established in 2013, Bone Research is a newly-founded English-language periodical that centers on the basic and clinical facets of bone biology, pathophysiology, and regeneration. It is dedicated to championing key findings emerging from both basic investigations and clinical research concerning bone-related topics. The journal's objective is to globally disseminate research in bone-related physiology, pathology, diseases, and treatment, contributing to the advancement of knowledge in this field.
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