G3BP1 inhibits ubiquitinated protein aggregations induced by p62 and USP10
G3BP1 inhibits ubiquitinated protein aggregations induced by p62 and USP10
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DOI：
10.1038/s41598-019-46237-1
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发表时间：
2019-09-09
影响因子：
4.6
通讯作者：
Fujii, Masahiro
中科院分区：
文献类型：
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作者：
Anisimov, Sergei;Takahashi, Masahiko;Fujii, Masahiro
细胞中泛素化蛋白聚集体的异常积累在包括帕金森病（PD）和囊性纤维化（CF）在内的几种退行性疾病的发病机制中起着关键作用。在这项研究中，我们发现Ras GTP酶激活蛋白结合蛋白1（G3 BP 1）抑制由p62和USP 10诱导的培养细胞中的泛素化蛋白聚集。p62是一种泛素受体，并且p62及其结合伴侣USP 10已显示出增强泛素化蛋白质聚集。G3 BP 1与p62和USP 10相互作用，抑制p62/USP 10诱导的蛋白聚集。G3 BP 1对蛋白质聚集的抑制作用靶向两种易于聚集的蛋白质，α-突触核蛋白和CFTR-Delta F508，它们分别是PD和CF的致病因子。G3 BP 1耗竭增加了泛素化α-突触核蛋白和CFTR-Δ F508蛋白的量。蛋白酶体报告表明G3 BP 1耗竭抑制蛋白酶体活性。我们在此提出的证据表明，G3 BP 1，p62和USP 10共同控制泛素化蛋白的毒性，通过控制泛素化和聚集。综上所述，这些结果表明，G3 BP 1，p62和USP 10可能是泛素化蛋白聚集障碍，包括PD和CF的治疗靶点。
The aberrant accumulation of ubiquitinated protein aggregates in cells plays a critical role in the pathogenesis of several degenerative diseases, including Parkinson disease (PD) and cystic fibrosis (CF). In this study, we found that Ras GTPase-activating protein-binding protein 1 (G3BP1) inhibits ubiquitinated protein aggregations induced by p62 and USP10 in cultured cells. p62 is a ubiquitin receptor, and p62 and its binding partner USP10 have been shown to augment ubiquitinated protein aggregation. G3BP1 interacted with p62 and USP10 and inhibited p62/USP10-induced protein aggregation. The G3BP1 inhibition of protein aggregations targeted two aggregation-prone proteins, a-synuclein and CFTR-Delta F508, which are causative factors of PD and CF, respectively. G3BP1 depletion increased the amounts of ubiquitinated alpha-synuclein and CFTR-Delta F508 protein. A proteasome reporter indicated that G3BP1 depletion inhibits the proteasome activity. We herein present evidence that G3BP1, p62 and USP10 together control ubiquitinated protein toxicity by controlling both ubiquitination and aggregation. Taken together, these results suggest that G3BP1, p62 and USP10 could be therapeutic targets for ubiquitinated protein aggregation disorders, including PD and CF.