Recognition of lumenal prion protein aggregates by post-ER quality control mechanisms is mediated by the preoctarepeat region of PrP
Recognition of lumenal prion protein aggregates by post-ER quality control mechanisms is mediated by the preoctarepeat region of PrP
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DOI：
10.1111/j.1600-0854.2004.0175.x
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发表时间：
2004-04-01
期刊：
影响因子：
4.5
通讯作者：
Schätzl, HM
中科院分区：
文献类型：
--
作者：
Gilch, S;Nunziante, M;Schätzl, HM
朊病毒病是一种致命的传染性神经退行性疾病，与细胞朊病毒蛋白（PrPc）的异常构象有关。我们以前已经表明，化合物苏拉明诱导聚集的完全成熟的PrPc后ER室，从而激活后ER质量控制机制，并防止细胞表面本地化的聚集PrP从高尔基体/TGN直接到溶酶体的细胞内重新路由的PrP。值得注意的是，药物诱导的PrP聚集体没有毒性，并且可以容易地被神经元细胞降解。在这里，我们专注于确定介导这些影响的PrP结构域。使用PrP缺失突变体，我们表明，细胞内的重新路由，但不聚集依赖于N-末端PrP（氨基酸23-90），更准确地说，在preocaterepeat结构域（氨基酸23-50）。PrP N-末端与GPI锚定蛋白Thy-1的融合不会引起嵌合蛋白的聚集或重新路由，表明N-末端仅在朊病毒蛋白聚集发生时在重新路由中是活跃的。插入一个区域与一个相当的一级结构中所包含的PrP parchromatogram prnd/doppel（aa 27-50）到N-末端删除PrP重新建立了重新路由表型。我们的数据揭示了一个重要的作用，为保守的preocatrepeat区域的PrP，即控制胞内贩运的错误折叠的PrP。
Prion diseases are fatal transmissible neurodegenerative disorders linked to an aberrant conformation of the cellular prion protein (PrPc). We have shown previously that the chemical compound suramin induced aggregation of fully matured PrPc in post-ER compartments, thereby, activating a post-ER quality control mechanism and preventing cell surface localization of PrP by intracellular re-routing of aggregated PrP from the Golgi/TGN directly to lysosomes. Of note, drug-induced PrP aggregates were not toxic and could easily be degraded by neuronal cells. Here, we focused on determining the PrP domains mediating these effects. Using PrP deletion mutants we show that intracellular re-routing but not aggregation depends on the N-terminal PrP (aa 23-90) and, more precisely, on the preoctarepeat domain (aa 23-50). Fusion of the PrP N-terminus to the GPI-anchored protein Thy-1 did not cause aggregation or re-routing of the chimeric protein, indicating that the N-terminus is only active in re-routing when prion protein aggregation occurs. Insertion of a region with a comparable primary structure contained in the PrP paralogue prnd/doppel (aa 27-50) into N-terminally deleted PrP re-established the re-routing phenotype. Our data reveal an important role for the conserved preoctarepeat region of PrP, namely controlling the intracellular trafficking of misfolded PrP.