Periz Goran, Lu Jiayin, Zhang Tao, Kankel Mark W, Jablonski Angela M, Kalb Robert, McCampbell Alexander, Wang Jiou
Department of Biochemistry and Molecular Biology and Department of Neuroscience, Bloomberg School of Public Health and School of Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America.
Biogen Idec, Cambridge, Massachusetts, United States of America.
PLoS Biol. 2015 Apr 2;13(4):e1002114. doi: 10.1371/journal.pbio.1002114. eCollection 2015 Apr.
Protein quality control is essential for clearing misfolded and aggregated proteins from the cell, and its failure is associated with many neurodegenerative disorders. Here, we identify two genes, ufd-2 and spr-5, that when inactivated, synergistically and robustly suppress neurotoxicity associated with misfolded proteins in Caenorhabditis elegans. Loss of human orthologs ubiquitination factor E4 B (UBE4B) and lysine-specific demethylase 1 (LSD1), respectively encoding a ubiquitin ligase and a lysine-specific demethylase, promotes the clearance of misfolded proteins in mammalian cells by activating both proteasomal and autophagic degradation machineries. An unbiased search in this pathway reveals a downstream effector as the transcription factor p53, a shared substrate of UBE4B and LSD1 that functions as a key regulator of protein quality control to protect against proteotoxicity. These studies identify a new protein quality control pathway via regulation of transcription factors and point to the augmentation of protein quality control as a wide-spectrum antiproteotoxicity strategy.
蛋白质质量控制对于清除细胞内错误折叠和聚集的蛋白质至关重要，其功能失调与许多神经退行性疾病相关。在此，我们鉴定出两个基因，ufd - 2和spr - 5，当它们失活时，能协同且有力地抑制秀丽隐杆线虫中与错误折叠蛋白质相关的神经毒性。分别编码泛素连接酶和赖氨酸特异性去甲基化酶的人类直系同源基因泛素化因子E4 B（UBE4B）和赖氨酸特异性去甲基化酶1（LSD1）的缺失，通过激活蛋白酶体和自噬降解机制促进哺乳动物细胞中错误折叠蛋白质的清除。对该通路的无偏搜索揭示了转录因子p53作为下游效应物，它是UBE4B和LSD1的共同底物，作为蛋白质质量控制的关键调节因子发挥作用以抵御蛋白毒性。这些研究通过转录因子的调控鉴定出一条新的蛋白质质量控制通路，并指出增强蛋白质质量控制作为一种广谱抗蛋白毒性策略。
