Impaired Protein Aggregate Handling and Clearance Underlie the Pathogenesis of p97/VCP-associated Disease
Impaired Protein Aggregate Handling and Clearance Underlie the Pathogenesis of p97/VCP-associated Disease
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DOI：
10.1074/jbc.m805517200
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发表时间：
2008-10-31
影响因子：
4.8
通讯作者：
Weihl, Conrad C.
中科院分区：
文献类型：
--
作者：
Ju, Jeong-Sun;Miller, Sara E.;Weihl, Conrad C.
p97/VCP的突变导致多系统疾病包涵体肌病、骨佩吉特病和额颞叶痴呆（IBMPFD）。p97/VCP是AAA+（与多种活性相关的ATP酶）蛋白家族的成员，并且已经涉及多种细胞过程。IBMPFD的一个病理特征是遍在蛋白化内含物，这表明p97/VCP的突变可能影响蛋白质降解。目前的研究表明，IBMPFD突变表达增加泛素化蛋白和蛋白酶体抑制的易感性。在IBMPFD突变体细胞中共表达的聚集倾向蛋白，如扩展的聚谷氨酰胺，导致聚集蛋白的增加，其定位于小的内含物，而不是单个核周侵略。这些小包涵体不能与自噬机制共定位。IBMPFD突变体与这些小内含物强烈结合，可能不允许它们运输到攻击基因组。这是由HDAC 6拯救的，HDAC 6是一种促进蛋白质聚集体自噬降解的p97/VCP结合蛋白。HDAC 6的表达可改善攻击性基因组的形成并保护IBMPFD突变细胞免受聚谷氨酰胺诱导的细胞死亡。我们的研究强调了蛋白质聚集体在退行性疾病中向包涵体运输的重要性以及包涵体形成的治疗益处。
Mutations in p97/VCP cause the multisystem disease inclusion body myopathy, Paget disease of the bone and frontotemporal dementia (IBMPFD). p97/VCP is a member of the AAA+ (ATPase associated with a variety of activities) protein family and has been implicated in multiple cellular processes. One pathologic feature in IBMPFD is ubiquitinated inclusions, suggesting that mutations in p97/VCP may affect protein degradation. The present study shows that IBMPFD mutant expression increases ubiquitinated proteins and susceptibility to proteasome inhibition. Co-expression of an aggregate prone protein such as expanded polyglutamine in IBMPFD mutant cells results in an increase in aggregated protein that localizes to small inclusions instead of a single perinuclear aggresome. These small inclusions fail to co-localize with autophagic machinery. IBMPFD mutants avidly bind to these small inclusions and may not allow them to traffic to an aggresome. This is rescued by HDAC6, a p97/VCP-binding protein that facilitates the autophagic degradation of protein aggregates. Expression of HDAC6 improves aggresome formation and protects IBMPFD mutant cells from polyglutamine-induced cell death. Our study emphasizes the importance of protein aggregate trafficking to inclusion bodies in degenerative diseases and the therapeutic benefit of inclusion body formation.