التفاصيل البيبلوغرافية
| العنوان: |
Pathogenic Mutations in the Valosin-containing Protein/p97(VCP) N-domain Inhibit the SUMOylation of VCP and Lead to Impaired Stress Response. |
| المؤلفون: |
Tao Wang1, Wangchao Xu1,2, Meiling Qin1, Yi Yang1,2, Puhua Bao1, Fuxiao Shen1, Zhenlin Zhang3, Jin Xu1 Jin.Xu@ion.ac.cn |
| المصدر: |
Journal of Biological Chemistry. 7/1/2016, Vol. 291 Issue 27, p14373-14384. 12p. |
| مصطلحات موضوعية: |
*GENETIC mutation, *ADENOSINE triphosphatase, *PROTEOLYSIS, *PHYSIOLOGICAL stress, *AUTOPHAGY, *DNA repair |
| مستخلص: |
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 inVCPcause 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-defectiveVCPfails 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. [ABSTRACT FROM AUTHOR] |
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