Inclusion body myopathy-associated mutations in p97/VCP impair endoplasmic reticulum-associated degradation
Inclusion body myopathy-associated mutations in p97/VCP impair endoplasmic reticulum-associated degradation
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DOI：
10.1093/hmg/ddi426
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发表时间：
2006-01-15
影响因子：
3.5
通讯作者：
Hanson, PI
中科院分区：
文献类型：
--
作者：
Weihl, CC;Dalal, S;Hanson, PI
AAA+ 蛋白（与多种细胞活动相关的 ATP 酶）p97/VCP（含缬氨肽蛋白）突变会导致显性遗传的包涵体肌病综合征，伴有佩吉特骨病和额颞叶痴呆 (IBMPFD)。 p97/VCP 是一种普遍表达的蛋白质，参与许多细胞过程，包括内质网相关降解 (ERAD)。 p97/VCP 有助于从内质网 (ER) 中提取泛素化蛋白，并促进它们递送至蛋白酶体。本研究重点关注疾病相关 p97/VCP 突变对该通路的影响。我们发现，含有最常见的 IBMPFD 相关突变 R155H 的 p97/VCP 具有正常的 ATP 酶活性和六聚体结构。然而，当在培养细胞中表达时，该突变体和第二个 IBMPFD 相关 p97/VCP 突变体都会增加泛素缀合蛋白的总体水平，并特别损害由 ERAD 途径处理的突变体 Delta F508-CFTR 的降解。这些效应与先前描述的 ATP 酶缺陷 p97/VCP 突变体的效应相似，表明 IBMPFD 突变会损害 p97/VCP 细胞功能。在一部分细胞中，IBMPFD 突变还促进含有 p97/VCP、泛素缀合物和 ER 驻留蛋白的聚集体的形成。未降解的突变体 Delta F508-CFTR 也在这些聚集体中积累。我们得出结论，p97/VCP 中的 IBMPFD 突变会破坏 ERAD，这可能导致 IBMPFD 的发病机制。
Mutations in the AAA+ protein (ATPase associated with a variety of cellular activities) p97/VCP (valosin-containing protein) cause a dominantly inherited syndrome of inclusion body myopathy with Paget's disease of the bone and fronto-temporal dementia (IBMPFD). p97/VCP is a ubiquitously expressed protein that participates in a number of cellular processes including endoplasmic reticulum-associated degradation (ERAD). p97/VCP aids in the extraction of ubiquitinated proteins from the endoplasmic reticulum (ER) and facilitates their delivery to the proteasome. This study focusses on the effects of disease-associated p97/VCP mutations on this pathway. We show that p97/VCP containing the most prevalent IBMPFD-associated mutation, R155H, has normal ATPase activity and hexameric structure. However, when expressed in cultured cells, both this and a second IBMPFD-associated p97/VCP mutant increase the overall level of ubiquitin-conjugated proteins and specifically impair degradation of mutant Delta F508-CFTR handled by the ERAD pathway. These effects are similar to those previously described for an ATPase deficient p97/VCP mutant and suggest that IBMPFD mutations impair p97/VCP cellular function. In a subset of cells, IBMPFD mutations also promote formation of aggregates that contain p97/VCP, ubiquitin conjugates and ER-resident proteins. Undegraded mutant Delta F508-CFTR also accumulates in these aggregates. We conclude that IBMPFD mutations in p97/VCP disrupt ERAD and that this may contribute to the pathogenesis of IBMPFD.