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JCB：中科院遗传发育所杨崇林和郭伟翔研究组合作揭示蛋白聚集体选择性自噬调控新机制

2017-04-19 杨崇林,郭伟翔 生物帮

蛋白聚集体选择性自噬
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2017年4月12日，国际著名细胞生物学期刊杂志《Journal of Cell biology》上在线发表了中国科学院遗传与发育生物学研究所杨崇林研究组和郭伟翔研究组合作的研究论文，论文题为The BEACH-containing protein WDR81 coordinates p62 and LC3C to promote aggrephagy。研究发现了蛋白聚集体通过选择性自噬清除过程中

2017年4月12日，国际著名细胞生物学期刊杂志《Journal of Cell biology》上在线发表了中国科学院遗传与发育生物学研究所杨崇林研究组和郭伟翔研究组合作的研究论文，论文题为The BEACH-containing protein WDR81 coordinates p62 and LC3C to promote aggrephagy。研究发现了蛋白聚集体通过选择性自噬清除过程中新的调控因子，并揭示了其作用机制。杨崇林研究组博士生刘学钊、博士后李洋为该论文的共同第一作者，杨崇林和郭伟翔为该论文的共同通讯作者。

错误折叠蛋白和蛋白聚集体的清除对于细胞稳态维持至关重要。蛋白聚集体可通过选择性细胞自噬而被清除，此过程被称为聚集体自噬(aggrephagy)。聚集体自噬由受体分子p62/SQSTM1与自噬体膜上的Atg8/LC3家族蛋白互作，对多泛素化蛋白识别而形成自噬体(autophagosome)，经与溶酶体融合后被降解。

杨崇林研究组在前期研究中，发现两个从秀丽线虫到人之间均为保守的蛋白：SORF-1/WDR91和SORF-2/WDR81。它们形成复合体，通过与磷脂酰肌醇3-磷酸激酶(PI3K)复合体的Beclin1亚基互作，进而抑制内吞体上PtdIns3P的生成，促进早期内吞体向晚期内吞体转换，从而使细胞内靶向溶酶体的运输得以顺利进行(Liu K et. al., J. Cell Biol. 212: 181-198, 2016)。该研究揭示了WDR81蛋白的一种新功能，即其作为衔接蛋白(Adaptor protein)，促进蛋白聚集体的选择性自噬。这一功能不同于此前已发现的WDR81-WDR91复合体在溶酶体运输通路的早-晚期内吞体转换中的作用。该研究发现WDR81被招募到泛素化的蛋白聚集体上，其缺失导致泛素化蛋白及其受体p62在细胞内大量累积。研究发现，WDR81通过其N端结合p62，促进泛素化蛋白与p62的结合。另一方面，WDR81通过其BEACH结构域中的LIR motif 特异地结合LC3C，促进泛素化蛋白对LC3C的募集。因此，WDR81一方面促进受体分子对泛素化蛋白聚集体的识别，另一方面与自噬体膜上的LC3C发生互作，使泛素化的蛋白聚集体通过自噬而被清除。

在特异性敲除WDR81小鼠的脑中，泛素化蛋白和p62 聚集体在皮层和纹状体神经元中明显累积，且新生小鼠的死亡率极高。人类WDR81突变可能导致CAMRQ2综合征，其表现为小脑发育缺陷、智障，四肢爬行，但病理机制未知。杨崇林研究组此前的研究与本项研究结果表明，WDR81突变导致细胞内运输障碍和变性蛋白聚集体的清除障碍，这可能是导致WDR81-相关的CAMRQ2综合征的主要原因。

(A)细胞中WDR81的缺失导致泛素化蛋白(Ub)和自噬受体分子p62的累积;(B)小鼠脑部缺失WDR81导致自噬受体分子p62的累积。

原始出处：

Xuezhao Liu，Yang Li，Xin Wang，Ruxiao Xing,et al.The BEACH-containing protein WDR81 coordinates p62 and LC3C to promote aggrephagy.jcb

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    2017-06-14 肉我只吃一口

    #选择性#

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    2017-12-06 zhangfenasdf

    #选择性自噬#

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    2017-07-07 gous

    #中科院#

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    2017-04-21 lxl1227

    正在探索中。。。。。。。。。。。。。。。。。。。。。

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    2017-04-21 neurowu

    #发育#

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