Abstract：
Ataxin-2 (Atx2) is a polyglutamine (polyQ) protein, in which abnormal expansion of the polyQ tract can trigger protein aggregation and consequently cause spinocerebellar ataxia type 2 (SCA2), but the mechanism underlying how Atx2 aggregation leads to proteinopathy remains elusive. Here, we investigate the molecular mechanism and cellular consequences of Atx2 aggregation by molecular cell biology approaches. We have revealed that either normal or polyQ-expanded Atx2 can sequester Raptor, a component of mammalian target of rapamycin complex 1 (mTORC1), into aggregates based on their specific interaction. Further research indicates that the polyQ tract and the N-terminal region (residues 1-784) of Atx2 are responsible for the specific sequestration. Moreover, this sequestration leads to suppression of the mTORC1 activity as represented by down-regulation of phosphorylated P70S6K, which can be reversed by overexpression of Raptor. As mTORC1 is a key regulator of autophagy, Atx2 aggregation and sequestration also induces autophagy by upregulating LC3-II and reducing phosphorylated ULK1 levels. This study proposes that Atx2 sequesters Raptor into aggregates, thereby impairing cellular mTORC1 signaling and inducing autophagy, and will be beneficial for a better understanding of the pathogenesis of SCA2 and other polyQ diseases.
摘要：
Ataxin-2（Atx2）是一种聚谷氨酰胺（polyQ）蛋白，其中polyQ束的异常扩张可以引发蛋白质聚集，从而导致脊髓小脑共济失调2型（SCA2），但是Atx2聚集导致蛋白质病的潜在机制仍然难以捉摸。这里,我们通过分子细胞生物学方法研究了Atx2聚集的分子机制和细胞后果。我们已经发现，无论是正常的还是polyQ扩展的Atx2都可以隔离Raptor，哺乳动物雷帕霉素靶复合物1（mTORC1）的成分，根据它们的特定相互作用转换成聚集体。进一步的研究表明，PolyQ区和Atx2的N末端区域（残基1-784）负责特异性螯合。此外，这种隔离导致mTORC1活性的抑制，如磷酸化P70S6K的下调，可以通过Raptor的过表达来逆转。由于mTORC1是自噬的关键调节因子，Atx2聚集和隔离还通过上调LC3-II和降低磷酸化ULK1水平来诱导自噬。这项研究提出Atx2将Raptor隔离成聚集体，从而损害细胞mTORC1信号并诱导自噬，这将有利于更好地理解SCA2和其他polyQ疾病的发病机制。
