Pathogenic Mutations in the Valosin-containing Protein/p97(VCP) N-domain Inhibit the SUMOylation of VCP and Lead to Impaired Stress Response

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	Pathogenic Mutations in the Valosin-containing Protein/p97(VCP) N-domain Inhibit the SUMOylation of VCP and Lead to Impaired Stress Response
	Wang, T; Xu, WC; Qin, ML; Yang, Y; Bao, PH; Shen, FX; Zhang, ZL; Xu, J
刊名	JOURNAL OF BIOLOGICAL CHEMISTRY
	2016
卷号	291 期号:27 页码:14373-14384
关键词	NEURODEGENERATIVE DISEASES AAA-ATPASE OXIDATIVE STRESS QUALITY-CONTROL PROTEIN VCP SUMO COMPLEX DEGRADATION PROTEOSTASIS MECHANISMS
通讯作者	Xu, J (reprint author), Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Neurosci, State Key Lab Neurosci, Shanghai 200031, Peoples R China.,Jin.Xu@ion.ac.cn
英文摘要	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.
学科主题	Biochemistry & Molecular Biology
WOS标题词	Biochemistry & Molecular Biology
语种	英语
WOS记录号	WOS:000379975100039
内容类型	期刊论文
源URL	[http://ir.sibs.ac.cn/handle/331001/4015]
专题	上海神经科学研究所_神经所(总)
推荐引用方式 GB/T 7714	Wang, T,Xu, WC,Qin, ML,et al. Pathogenic Mutations in the Valosin-containing Protein/p97(VCP) N-domain Inhibit the SUMOylation of VCP and Lead to Impaired Stress Response[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2016,291(27):14373-14384.
APA	Wang, T.,Xu, WC.,Qin, ML.,Yang, Y.,Bao, PH.,...&Xu, J.(2016).Pathogenic Mutations in the Valosin-containing Protein/p97(VCP) N-domain Inhibit the SUMOylation of VCP and Lead to Impaired Stress Response.JOURNAL OF BIOLOGICAL CHEMISTRY,291(27),14373-14384.
MLA	Wang, T,et al."Pathogenic Mutations in the Valosin-containing Protein/p97(VCP) N-domain Inhibit the SUMOylation of VCP and Lead to Impaired Stress Response".JOURNAL OF BIOLOGICAL CHEMISTRY 291.27(2016):14373-14384.