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Hydrogen peroxide triggers the proteolytic cleavage and the inactivation of calcineurin

Ji-Eun Lee1, Hyungsoo Kim, Hyonchol Jang

  • 1Department of Biochemistry and Molecular Biology, Cancer Research Institute, Interdisciplinary Program in Genetic Engineering, Seoul National University College of Medicine, Seoul, South Korea.

Journal of Neurochemistry
|January 16, 2007
PubMed

Insights

Reactive oxygen species (ROS) inactivate calcineurin (CN) by triggering its proteolytic cleavage, a process independent of calcium influx and potentially mediated by lysosomal proteases, impacting ROS-related diseases.

Area of Science:

  • Neuroscience
  • Biochemistry
  • Cell Biology

Background:

  • Increased reactive oxygen species (ROS) levels correlate with reduced calcineurin (CN) activity in oxidative and neuropathological conditions.
  • The precise molecular mechanism of ROS-induced calcineurin inactivation remains largely unknown.

Purpose of the Study:

  • To elucidate the molecular mechanism by which hydrogen peroxide, a key ROS, inactivates calcineurin.
  • To investigate the role of calcium influx and lysosomal pathways in this inactivation process.

Main Methods:

  • Treatment of primary mouse cortical neurons and other cell types with hydrogen peroxide and Abeta(1-42) peptide.
  • Enzymatic activity assays for calcineurin.
  • Analysis of calcineurin cleavage products and localization.
  • Pharmacological inhibition using chloroquine.

Main Results:

  • Hydrogen peroxide induced proteolytic cleavage of calcineurin in various cell types, leading to decreased enzymatic activity.
  • Calcineurin inactivation was not dependent on calcium influx.
  • Chloroquine partially inhibited calcineurin cleavage, suggesting involvement of lysosomal proteases.
  • Cleavage occurred within the catalytic domain, rendering calcineurin unable to dephosphorylate nuclear factor of activated T cells.

Conclusions:

  • Hydrogen peroxide inactivates calcineurin through proteolysis, specifically by cleavage within its catalytic domain.
  • This mechanism involves lysosomal proteases and is independent of calcium signaling.
  • The findings provide a molecular basis for calcineurin dysfunction in ROS-related diseases.

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