Wang T, Xu W, Qin M, Yang Y, Bao P, Shen F, Zhang Z, Xu J

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. ...

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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.

Date: Jul. 01, 2016

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