Valosin-containing protein (VCP) is required for autophagy and is disrupted in VCP disease.
Valosin-containing protein (VCP) is required for autophagy and is disrupted in VCP disease.
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DOI：
10.1083/jcb.200908115
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发表时间：
2009-12-14
期刊：
影响因子：
--
通讯作者：
Weihl CC
中科院分区：
文献类型：
--
作者：
Ju JS;Fuentealba RA;Miller SE;Jackson E;Piwnica-Worms D;Baloh RH;Weihl CC
自噬体的积累，因为受损的自噬过程中含有valosin-containing蛋白（VCP）相关的痴呆症是由VCP的缺乏或活性降低的解释。含Valosin-containing蛋白（VCP）的突变导致包涵体肌病（IBM）、骨的佩吉特病和额颞叶痴呆（IBMPFD）。患者肌肉有退化的纤维、镶边空泡（RV）和含有泛素和TDP-43（TARDNA结合蛋白43）的肌浆内含物。在这项研究中，我们发现IBMPFD肌肉也积累了自噬体相关蛋白，Map 1-LC 3（LC 3）和p62/隔离体，这些蛋白定位于RV。为了测试VCP是否参与自噬，我们沉默VCP或表达腺苷三磷酸酶失活的VCP。在基础条件下，VCP活性的丧失导致自噬体积累。自噬诱导后，这些自噬体不能成熟为自溶体并降解LC 3。类似地，IBMPFD突变体VCP在细胞和动物中的表达导致非降解性自噬体的积累，其在RV处聚结并且不能降解聚集的蛋白质。有趣的是，TDP-43在自噬抑制后在胞质溶胶中积累，类似于IBMPFD突变体表达后所见。这些数据表明VCP与自噬有关，并表明受损的自噬解释了IBMPFD肌肉中观察到的病理学，包括TDP-43积累。
Accumulation of autophagosomes because of impaired autophagy during valosin-containing protein (VCP)–linked dementia is explained by the absence or reduced activity of VCP. Mutations in valosin-containing protein (VCP) cause inclusion body myopathy (IBM), Paget's disease of the bone, and frontotemporal dementia (IBMPFD). Patient muscle has degenerating fibers, rimmed vacuoles (RVs), and sarcoplasmic inclusions containing ubiquitin and TDP-43 (TARDNA-binding protein 43). In this study, we find that IBMPFD muscle also accumulates autophagosome-associated proteins, Map1-LC3 (LC3), and p62/sequestosome, which localize to RVs. To test whether VCP participates in autophagy, we silenced VCP or expressed adenosine triphosphatase–inactive VCP. Under basal conditions, loss of VCP activity results in autophagosome accumulation. After autophagic induction, these autophagosomes fail to mature into autolysosomes and degrade LC3. Similarly, IBMPFD mutant VCP expression in cells and animals leads to the accumulation of nondegradative autophagosomes that coalesce at RVs and fail to degrade aggregated proteins. Interestingly, TDP-43 accumulates in the cytosol upon autophagic inhibition, similar to that seen after IBMPFD mutant expression. These data implicate VCP in autophagy and suggest that impaired autophagy explains the pathology seen in IBMPFD muscle, including TDP-43 accumulation.
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