Sequestosome 1/p62 shuttles polyubiquitinated tau for proteasomal degradation
Sequestosome 1/p62 shuttles polyubiquitinated tau for proteasomal degradation
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DOI：
10.1111/j.1471-4159.2005.03181.x
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发表时间：
2005-07-01
影响因子：
4.7
通讯作者：
Wooten, MW
中科院分区：
文献类型：
--
作者：
Babu, JR;Geetha, T;Wooten, MW
从包括阿尔茨海默病（AD）在内的几种神经退行性疾病中分离的包涵体的特征在于泛素阳性蛋白质聚集体。采用共聚焦和免疫电子显微镜，我们发现，泛素相关蛋白螯合体1/p62，共定位到聚集体分离自AD，但不控制大脑，沿着与E3泛素连接酶，TRAF 6。这种相互作用可以通过在HEK 293细胞中共转染来重现。采用体外和体内方法，发现tau是TRAF 6的底物，具有赖氨酸63聚泛素链。此外，与野生型相比，从TRAF 6敲除小鼠的脑中回收的tau蛋白未被泛素化。Tau降解通过泛素-蛋白酶体途径发生，并且依赖于K63-聚泛素链或p62。在p62基因敲除小鼠的脑裂解物中，tau不能与蛋白酶体亚基Rpt 1相互作用，从而表明tau需要p62穿梭到蛋白酶体。我们的研究结果表明，p62通过其乌巴结构域与K63-polyubiquitinated tau相互作用，并在调节tau蛋白酶体降解中发挥新的作用。我们提出了一个模型，其中无论是在p62表达下降或蛋白酶体活性降低可能有助于积累不溶性/聚集K63-polyubiquitinated tau蛋白。
Inclusions isolated from several neurodegenerative diseases, including Alzheimer's disease (AD), are characterized by ubiquitin-positive proteinaceous aggregates. Employing confocal and immunoelectron microscopy, we find that the ubiquitin-associating protein sequestosome1/p62, co-localizes to aggregates isolated from AD but not control brain, along with the E3 ubiquitin ligase, TRAF6. This interaction could be recapitulated by co-transfection in HEK293 cells. Employing both in vitro and in vivo approaches, tau was found to be a substrate of the TRAF6, possessing lysine 63 polyubiquitin chains. Moreover, tau recovered from brain of TRAF6 knockout mice, compared with wild type, was not ubiquitinated. Tau degradation took place through the ubiquitin-proteasome pathway and was dependent upon either the K63-polyubiquitin chains or upon p62. In brain lysates of p62 knockout mice, tau fails to co-interact with Rpt1, a proteasomal subunit, thereby indicating a requirement for p62 shuttling of tau to the proteasome. Our results demonstrate that p62 interacts with K63-polyubiquitinated tau through its UBA domain and serves a novel role in regulating tau proteasomal degradation. We propose a model whereby either a decline in p62 expression or a decrease in proteasome activity may contribute to accumulation of insoluble/aggregated K63-polyubiquitinated tau.