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Vaccinia-related kinase 2 modulates role of dysbindin by regulating protein stability

Young-Hun Jeong1, Jung-Hyun Choi1, Dohyun Lee1,2

  • 1Department of Life Sciences, Pohang University of Science and Technology, Pohang, Korea.

Journal of Neurochemistry
|August 1, 2018
PubMed

Insights

Vaccinia-related kinase 2 (VRK2) phosphorylates dysbindin, a protein linked to schizophrenia. This phosphorylation reduces dysbindin stability and neurite outgrowth, offering new insights into neurodegenerative disease mechanisms.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Biochemistry

Background:

  • Vaccinia-related kinase 2 (VRK2) is a kinase implicated in neurodegenerative disorders like schizophrenia.
  • Dysbindin is a known risk factor for schizophrenia, with reduced expression in patients and roles in neurite outgrowth and NMDA receptor signaling.
  • The specific substrates and functions of VRK2 remain largely unknown.

Purpose of the Study:

  • To identify novel interacting proteins of VRK2.
  • To investigate whether VRK2 phosphorylates dysbindin and the functional consequences of this interaction.
  • To explore the role of VRK2-dysbindin interaction in neuronal function relevant to schizophrenia.

Main Methods:

  • Co-immunoprecipitation to identify VRK2-interacting proteins.
  • In vitro kinase assays to determine VRK2 phosphorylation sites on dysbindin.
  • Western blotting to assess ubiquitination and protein stability.
  • Cell culture experiments (SH-SY5Y cells, mouse hippocampal neurons) to evaluate effects on neurite outgrowth and NMDA receptor subunit expression.

Main Results:

  • Dysbindin was identified as a novel interacting protein of VRK2.
  • VRK2 was shown to phosphorylate dysbindin at Serine 297 and Serine 299.
  • VRK2-mediated phosphorylation enhanced dysbindin ubiquitination, decreasing its protein stability.
  • Overexpression of VRK2 reduced retinoic acid-induced neurite outgrowth in SH-SY5Y cells.
  • A phosphomimetic dysbindin mutant impaired neurite outgrowth and affected surface expression of N-methyl-D-aspartate 2A (a subunit of NMDA receptor).

Conclusions:

  • This study reveals VRK2 as a regulator of dysbindin through phosphorylation.
  • The findings elucidate a novel molecular mechanism linking VRK2 and dysbindin, both implicated in schizophrenia.
  • This provides a foundation for understanding the pathogenesis of schizophrenia and developing therapeutic strategies.
Keywords:
NR2A surface expressionVRK2dysbindinneurite outgrowthphosphorylationprotein stability

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