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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\u2010expanded 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\u2010terminal region (residues 1\u2013784) of Atx2 are responsible for the specific sequestration. Moreover, this sequestration leads to suppression of the mTORC1 activity as represented by down\u2010regulation 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\u2010II 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.<\/jats:p>","DOI":"10.1111\/febs.17081","type":"journal-article","created":{"date-parts":[[2024,2,3]],"date-time":"2024-02-03T16:35:11Z","timestamp":1706978111000},"page":"1795-1812","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Ataxin\u20102 sequesters Raptor into aggregates and impairs cellular <scp>mTORC1<\/scp> signaling"],"prefix":"10.1111","volume":"291","author":[{"given":"Ya\u2010Jun","family":"Liu","sequence":"first","affiliation":[{"name":"State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science Chinese Academy of Sciences  Shanghai China"},{"name":"University of Chinese Academy of 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