VCP/p97 is essential for maturation of ubiquitin-containing autophagosomes and this function is impaired by mutations that cause IBMPFD.
VCP/p97 is essential for maturation of ubiquitin-containing autophagosomes and this function is impaired by mutations that cause IBMPFD.
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DOI：
10.4161/auto.6.2.11014
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发表时间：
2010-02
期刊：
影响因子：
13.3
通讯作者：
Taylor JP
中科院分区：
文献类型：
--
作者：
Tresse E;Salomons FA;Vesa J;Bott LC;Kimonis V;Yao TP;Dantuma NP;Taylor JP
VCP （VCP/p97）是一种普遍表达的AAA+- atp酶家族成员，该家族是一种伴侣样蛋白，可调节许多细胞过程，包括染色质去浓缩、同型膜融合和蛋白酶体对泛素依赖性蛋白的降解。VCP突变可引起包括包涵体肌病、骨佩吉特病和额颞叶痴呆（IBMPFD）在内的多系统退行性疾病。本研究表明VCP对自噬体成熟至关重要。我们生成了稳定表达双标记LC3 （mCherry-EGFP-LC3）的细胞，可以监测自噬体的成熟。我们确定，通过rnai介导的VCP缺失或显性阴性VCP的过度表达导致未成熟自噬囊泡的显著积累，其中一些囊泡异常大，酸化并表现出组织蛋白酶B活性。此外，疾病相关VCP突变体（R155H和A232E）的表达也会导致这种自噬缺陷。研究发现，在基础条件下和蛋白酶体抑制的细胞中，VCP对自噬体成熟至关重要，但在饥饿的细胞中则不然，这表明VCP可能是泛素化底物自噬降解的选择性需要。事实上，大量积累的自噬囊泡含有泛素阳性成分，这一特征在饥饿或巴菲霉素a治疗后积累的自噬囊泡中没有观察到。最后，我们在IBMPFD患者的成肌细胞中发现了大量的、大的LAMP-1和LAMP-2阳性液泡和LC3-II的积累。我们得出结论，VCP对含泛素的自噬体的成熟至关重要，该功能的缺陷可能有助于IBMPFD的发病机制。
VCP (VCP/p97) is a ubiquitously expressed member of the AAA+-ATPase family of chaperone-like proteins that regulates numerous cellular processes including chromatin decondensation, homotypic membrane fusion, and ubiquitin-dependent protein degradation by the proteasome. Mutations in VCP cause a multisystem degenerative disease consisting of inclusion body myopathy, Paget’s disease of bone, and frontotemporal dementia (IBMPFD). Here we show that VCP is essential for autophagosome maturation. We generated cells stably expressing dual-tagged LC3 (mCherry-EGFP-LC3) which permit monitoring of autophagosome maturation. We determined that VCP deficiency by RNAi-mediated knockdown or over-expression of dominant-negative VCP results in significant accumulation of immature autophagic vesicles, some of which are abnormally large, acidified and exhibit cathepsin B activity. Furthermore, expression of disease-associated VCP mutants (R155H and A232E) also causes this autophagy defect. VCP was found to be essential to autophagosome maturation under basal conditions and in cells challenged by proteasome inhibition, but not in cells challenged by starvation, suggesting that VCP might be selectively required for autophagic degradation of ubiquitinated substrates. Indeed, a high percentage of the accumulated autophagic vesicles contain ubiquitin-positive contents, a feature that is not observed in autophagic vesicles that accumulate following starvation or treatment with Bafilomycin A. Finally, we show accumulation of numerous, large LAMP-1 and LAMP-2 –positive vacuoles and accumulation of LC3-II in myoblasts derived from patients with IBMPFD. We conclude that VCP is essential for maturation of ubiquitin-containing autophagosomes and that defect in this function may contribute to IBMPFD pathogenesis.
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