Cellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur, Rajasthan, India 342011.
Sci Rep. 2013;3:1972. doi: 10.1038/srep01972.
Impairment in the elimination of misfolded proteins generates cellular toxicity and leads to various late-onset neurodegenerative diseases. However, the mechanisms by which cells recognize abnormal cellular proteins for selective clearance remain unknown. Lack of the mahogunin ring finger-1 (MGRN1) E3 ubiquitin ligase in mice causes the development of age-dependent spongiform neurodegeneration. Here, we report for the first time that the MGRN1 E3 ubiquitin ligase interacts and nicely co-localizes with the cytosolic molecular chaperone Hsp70. The expression of MGRN1 increased following exposure to a variety of stressors. The inhibition of autophagy not only elevated endogenous MGRN1 levels but also caused MGRN1 to be recruited to cytosolic ubiquitin-positive inclusion bodies. Finally, we showed that the overexpression of MGRN1 protects against cell death mediated by oxidative and endoplasmic reticulum stress. These data suggest that MGRN1 selectively targets misfolded proteins for degradation and may exhibit viable therapeutic potential for the treatment of spongiform neurodegeneration.
错误折叠蛋白的清除功能受损会产生细胞毒性，并导致各种迟发性神经退行性疾病。然而，细胞识别异常细胞蛋白以进行选择性清除的机制尚不清楚。在缺乏 mahogunin 环指蛋白 1 (MGRN1) E3 泛素连接酶的情况下，小鼠会发生年龄依赖性海绵状神经退行性变。在这里，我们首次报道 MGRN1 E3 泛素连接酶与细胞质分子伴侣 Hsp70 相互作用并很好地共定位。暴露于各种应激源后，MGRN1 的表达增加。自噬的抑制不仅使内源性 MGRN1 水平升高，而且还导致 MGRN1 被募集到细胞质泛素阳性包涵体中。最后，我们表明，MGRN1 的过表达可防止氧化应激和内质网应激介导的细胞死亡。这些数据表明，MGRN1 选择性地靶向错误折叠的蛋白质进行降解，并且可能在治疗海绵状神经退行性变方面具有可行的治疗潜力。
