S-Glutathionylation of Keap1: a new role for glutathione S-transferase pi in neuronal protection

FEBS Lett. 2016 May;590(10):1455-66. doi: 10.1002/1873-3468.12177. Epub 2016 May 3.

Abstract

Oxidative stress is a key pathological feature of Parkinson's disease (PD). Glutathione S-transferase pi (GSTP) is a neuroprotective antioxidant enzyme regulated at the transcriptional level by the antioxidant master regulator nuclear factor-erythroid 2-related factor 2 (Nrf2). Here, we show for the first time that upon MPTP-induced oxidative stress, GSTP potentiates S-glutathionylation of Kelch-like ECH-associated protein 1 (Keap1), an endogenous repressor of Nrf2, in vivo. S-glutathionylation of Keap1 leads to Nrf2 activation and subsequently increases expression of GSTP. This positive feedback regulatory loop represents a novel mechanism by which GSTP elicits antioxidant protection in the brain.

Keywords: Glutathione S-Transferase pi; Nrf2-Keap1 pathway; S-glutathionylation.

Publication types

  • Letter
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / adverse effects*
  • Animals
  • Brain / metabolism*
  • Feedback, Physiological
  • Gene Expression Regulation
  • Glutathione / metabolism
  • Glutathione S-Transferase pi / genetics
  • Glutathione S-Transferase pi / metabolism*
  • Kelch-Like ECH-Associated Protein 1 / chemistry
  • Kelch-Like ECH-Associated Protein 1 / metabolism*
  • Mice
  • Models, Molecular
  • Molecular Docking Simulation
  • NF-E2-Related Factor 2 / chemistry
  • NF-E2-Related Factor 2 / metabolism*
  • Oxidative Stress
  • Protein Binding

Substances

  • Keap1 protein, mouse
  • Kelch-Like ECH-Associated Protein 1
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • Glutathione S-Transferase pi
  • Gstp1 protein, mouse
  • Glutathione