p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death.
p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death.
复制标题
p62/SQSTM1形成自噬降解的蛋白质聚集体，并对亨廷顿蛋白诱导的细胞死亡具有保护作用。
DOI：
10.1083/jcb.200507002
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发表时间：
2005-11-21
影响因子：
7.8
通讯作者：
Johansen, Terje
中科院分区：
文献类型：
--
作者：
Bjorkoy, Geir;Lamark, Trond;Brech, Andreas;Outzen, Heidi;Perander, Maria;Overvatn, Aud;Stenmark, Harald;Johansen, Terje
泛素化蛋白聚集体的自噬降解对于细胞存活是重要的，但尚不清楚自噬机制如何识别这种聚集体。在这项研究中，我们报告说，聚合的多聚泛素结合蛋白p62/SQSTM 1产生蛋白体，无论是居住在细胞质和细胞核内或发生自噬体和溶酶体结构内的自由。自噬的抑制导致p62小体的大小和数量以及p62蛋白水平的增加。自噬标记轻链3（LC 3）与p62体共定位，并与p62共免疫沉淀，表明这两种蛋白质参与相同的复合物。在饥饿条件下，p62的耗竭抑制LC 3向自噬体的募集。引人注目的是，p62和LC 3形成了一个外壳周围的突变亨廷顿蛋白的聚集体。p62蛋白水平的降低或p62功能的干扰显著增加了由突变亨廷顿蛋白的表达诱导的细胞死亡。我们认为，p62可能，通过LC 3，参与连接多泛素化蛋白聚集体的自噬机制。
Autophagic degradation of ubiquitinated protein aggregates is important for cell survival, but it is not known how the autophagic machinery recognizes such aggregates. In this study, we report that polymerization of the polyubiquitin-binding protein p62/SQSTM1 yields protein bodies that either reside free in the cytosol and nucleus or occur within autophagosomes and lysosomal structures. Inhibition of autophagy led to an increase in the size and number of p62 bodies and p62 protein levels. The autophagic marker light chain 3 (LC3) colocalized with p62 bodies and coimmunoprecipitated with p62, suggesting that these two proteins participate in the same complexes. The depletion of p62 inhibited recruitment of LC3 to autophagosomes under starvation conditions. Strikingly, p62 and LC3 formed a shell surrounding aggregates of mutant huntingtin. Reduction of p62 protein levels or interference with p62 function significantly increased cell death that was induced by the expression of mutant huntingtin. We suggest that p62 may, via LC3, be involved in linking polyubiquitinated protein aggregates to the autophagy machinery.