VRK3-mediated nuclear localization of HSP70 prevents glutamate excitotoxicity-induced apoptosis and Aβ accumulation via enhancement of ERK phosphatase VHR activity.

Haengjin Song,Kyong-Tai Kim,Wanil Kim,Sung-Hoon Kim

doi:10.1038/srep38452

Abstract

Most of neurodegenerative disorders are associated with protein aggregation. Glutamate-induced excitotoxicity and persistent extracellular signal-regulated kinase (ERK) activation are also implicated in neurodegenerative diseases. Here, we found that vaccinia-related kinase 3 (VRK3) facilitates nuclear localization of glutamate-induced heat shock protein 70 (HSP70). Nuclear HSP70 leads to enhancement of vaccinia H1-related phosphatase (VHR) activity via protein-protein interaction rather than its molecular chaperone activity, thereby suppressing excessive ERK activation. Moreover, glutamate-induced ERK activation stimulates the expression of HSP70 and VRK3 at the transcriptional level. Downregulation of either VRK3 or HSP70 rendered cells vulnerable to glutamate-induced apoptosis. Overexpression of HSP70 fused to a nuclear localization signal attenuated apoptosis more than HSP70 alone. The importance of nuclear localization of HSP70 in the negative regulation of glutamate-induced ERK activation was further confirmed in VRK3-deficient neurons. Importantly, we showed a positive correlation between levels of VRK3 and HSP70 in the progression of Alzheimer’s and Parkinson’s diseases in humans, and neurons with HSP70 nuclear localization exhibited less Aβ accumulation in brains from patients with Alzheimer’s disease. Therefore, HSP70 and VRK3 could potentially serve as diagnostic and therapeutic targets in neurodegenerative diseases.

Highlights

Endoplasmic reticulum, and the mitochondria[14]
Excitotoxicity caused by excessive activation of glutamate receptors, impairment of intracellular calcium homeostasis, increased reactive oxygen species, persistent ERK activation, and protein aggregation are implicated in neurodegenerative diseases such as Alzheimer’s disease (AD) and PD25,30,37,46–48
We showed that VRK3 facilitates nuclear localization of HSP70 induced by glutamate stimulation, and nuclear HSP70 enhances vaccinia H1-related phosphatase (VHR) phosphatase activity through direct binding, leading to suppression of sustained ERK activation and apoptotic cell death (Fig. 6d)

Summary

Introduction

Endoplasmic reticulum, and the mitochondria[14]. The expression of HSP70 is very low under normal physiological conditions, but three members of HSP70 family are induced in response to stress[6], with heat shock stress inducing their rapid and transient relocation to the nucleus[15]. Excessive activation of glutamate receptors impairs intracellular calcium homeostasis, increases generation of reactive oxygen species, and alters the activation of kinases, including ERK 1/2, and proteases that degrade proteins, membranes, and nucleic acids[30]. This phenomenon, referred to as ‘glutamate neurotoxicity’, results in damage to dendrites and even cell death. Results from VRK3-deficient neurons further confirmed the role of HSP70 nuclear localization in the regulation of glutamate-induced prolonged ERK activation that triggers cell death. We conclude that VRK3-mediated nuclear localization of HSP70 plays a neuroprotective role by reducing glutamate-induced prolonged ERK activity that causes cell death

Methods

Results

Conclusion