Pathogenic Mutations in the Valosin-containing Protein/p97(VCP) N-domain Inhibit the SUMOylation of VCP and Lead to Impaired Stress Response
Pathogenic Mutations in the Valosin-containing Protein/p97(VCP) N-domain Inhibit the SUMOylation of VCP and Lead to Impaired Stress Response
复制标题
含 Valosin 的蛋白/p97(VCP) N 结构域的致病突变抑制 VCP 的 SUMO 化并导致应激反应受损
DOI：
10.1074/jbc.m116.729343
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发表时间：
2016-07-01
影响因子：
4.8
通讯作者：
Xu, Jin
中科院分区：
文献类型：
--
作者：
Wang, Tao;Xu, Wangchao;Xu, Jin
Valosin-containing protein/p97（VCP）是一种六聚三磷酸腺苷酶，在内质网应激过程中对蛋白质降解至关重要。它调节多种细胞功能，包括自噬、染色质重塑和DNA修复。此外，VCP突变可引起包涵体肌病、骨Paget病、额颞叶痴呆（IBMPFD）以及肌萎缩性侧索硬化症。然而，胁迫下VCP的活性是如何调控的，致病突变是如何影响VCP功能的，目前还不清楚。本研究表明，VCP的小泛素样修饰子(SUMO)-酰化是一种正常的应激反应，受到n结构域致病突变的抑制。在氧化和内质网应激条件下，VCP的SUMOylation促进了VCP向应激颗粒和细胞核的分布，促进了VCP六聚体的组装。相反，VCP n结构域的致病性突变导致胁迫下sumo化降低和VCP六聚体形成减弱。VCP的sumo化缺陷也导致辅因子结合改变和内质网相关蛋白降解减弱。此外，sumo缺陷的VCP不能保护果蝇免受应激诱导的毒性。因此，我们的研究结果揭示了SUMOylation作为一个分子信号开关，在应激反应中调节VCP的分布和功能，并表明致病性突变引起的VCP SUMOylation缺失会使细胞容易受到应激损伤。
Valosin-containing protein/p97(VCP) is a hexameric ATPase vital to protein degradation during endoplasmic reticulum stress. It regulates diverse cellular functions including autophagy, chromatin remodeling, and DNA repair. In addition, mutations in VCP cause inclusion body myopathy, Paget disease of the bone, and frontotemporal dementia (IBMPFD), as well as amyotrophic lateral sclerosis. Nevertheless, how the VCP activities were regulated and how the pathogenic mutations affect the function of VCP during stress are not unclear. Here we show that the small ubiquitin-like modifier (SUMO)-ylation of VCP is a normal stress response inhibited by the disease-causing mutations in the N-domain. Under oxidative and endoplasmic reticulum stress conditions, the SUMOylation of VCP facilitates the distribution of VCP to stress granules and nucleus, and promotes the VCP hexamer assembly. In contrast, pathogenic mutations in the VCP N-domain lead to reduced SUMOylation and weakened VCP hexamer formation upon stress. Defective SUMOylation of VCP also causes altered co-factor binding and attenuated endoplasmic reticulum-associated protein degradation. Furthermore, SUMO-defective VCP fails to protect against stress-induced toxicity in Drosophila. Therefore, our results have revealed SUMOylation as a molecular signaling switch to regulate the distribution and functions of VCP during stress response, and suggest that deficiency in VCP SUMOylation caused by pathogenic mutations will render cells vulnerable to stress insults.