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The Weakened Interaction Between HECTD4 and GluN2B in Ischemic Stroke Promotes Calcium Overload and Brain Injury

Yi-Yue Zhang1,2, Xiao-Yan Yang1,2, Hui-Qi Liu3

  • 1Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China.

Molecular Neurobiology
|December 17, 2022
PubMed

Insights

Downregulation of HECTD4 in ischemic stroke increases brain injury by activating GluN2B. This involves reduced ubiquitination of GluN2B and MALT1, leading to calcium overload and neuronal damage.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Biochemistry

Background:

  • Glutamate receptor ionotropic NMDA 2B (GluN2B) is crucial in excitotoxicity and calcium overload.
  • HECT domain E3 ubiquitin protein ligase 4 (HECTD4) and mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) are implicated in brain function.

Purpose of the Study:

  • To investigate the interplay between HECTD4, GluN2B, and MALT1 in the context of ischemic stroke brain injury.
  • To elucidate the molecular mechanisms underlying HECTD4's role in regulating GluN2B activity and neuronal damage.

Main Methods:

  • Establishment of an ischemic stroke model in rats (2h ischemia, 24h reperfusion).
  • Analysis of protein expression, phosphorylation, and ubiquitination levels (HECTD4, GluN2B, MALT1, STEP61).
  • In vitro experiments involving nerve cells subjected to hypoxia or NMDA, with HECTD4 knockdown and MALT1 inhibition/siRNA.

Main Results:

  • Ischemic stroke led to HECTD4 downregulation and MALT1 upregulation, increased GluN2B phosphorylation, and weakened HECTD4-GluN2B interaction.
  • HECTD4 knockdown exacerbated injury, reducing GluN2B/MALT1 ubiquitination and increasing calcium levels.
  • MALT1 inhibition reduced STEP61 degradation, decreased GluN2B phosphorylation, lowered calcium, and mitigated brain injury.

Conclusions:

  • Downregulation of HECTD4 in ischemic stroke contributes to calcium overload and brain injury.
  • This occurs via direct and indirect activation of GluN2B, involving reduced ubiquitination of GluN2B and MALT1.
  • Targeting MALT1 may offer a therapeutic strategy to reduce brain damage in ischemic stroke.
Keywords:
Calcium overloadGluN2BHECTD4Ischemic strokeMALT1Ubiquitination

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