The acetylation of RelA in Lys310 dictates the NF-κB-dependent response in post-ischemic injury

A. Lanzillotta, I. Sarnico, R. Ingrassia, F. Boroni, C. Branca, M. Benarese, G. Faraco, F. Blasi, A. Chiarugi, P. Spano, M. Pizzi

Research output: Contribution to journalArticle

Abstract

The activation of nuclear factor kappa B (NF-κB) p50/RelA is a key event in ischemic neuronal injury, as well as in brain ischemic tolerance. We tested whether epigenetic mechanisms affecting the acetylation state of RelA might discriminate between neuroprotective and neurotoxic activation of NF-κB during ischemia. NF-κB activation and RelA acetylation were investigated in cortices of mice subjected to preconditioning brain ischemia or lethal middle cerebral artery occlusion (MCAO) and primary cortical neurons exposed to preconditioning or lethal oxygen-glucose deprivation (OGD). In mice subjected to MCAO and in cortical neurons exposed to lethal OGD, activated RelA displayed a high level of Lys310 acetylation in spite of reduced total acetylation. Also, acetylated RelA on Lys310 interacted strongly with the CREB-binding protein (CBP). Conversely, RelA activated during preconditioning ischemia appeared deacetylated on Lys310. Overexpressing RelA increased Bim promoter activity and neuronal cell death both induced by lethal OGD, whereas overexpressing the acetylation-resistant RelA-K310R, carrying a mutation from Lys310 to arginine, prevented both responses. Pharmacological manipulation of Lys310 acetylation by the sirtuin 1 activator resveratrol repressed the activity of the Bim promoter and reduced the neuronal cell loss. We conclude that the acetylation of RelA in Lys310 dictates NF-jB-dependent pro-apoptotic responses and represents a suitable target to dissect pathological from neuroprotective NF-jB activation in brain ischemia..

Original languageEnglish
Article numbere96
JournalCell Death and Disease
Volume1
Issue number11
DOIs
Publication statusPublished - Nov 2010

Keywords

  • Ischemic preconditioning
  • MCAO
  • OGD
  • RelA acetylation

ASJC Scopus subject areas

  • Cell Biology
  • Immunology
  • Cancer Research
  • Cellular and Molecular Neuroscience
  • Medicine(all)

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    Lanzillotta, A., Sarnico, I., Ingrassia, R., Boroni, F., Branca, C., Benarese, M., Faraco, G., Blasi, F., Chiarugi, A., Spano, P., & Pizzi, M. (2010). The acetylation of RelA in Lys310 dictates the NF-κB-dependent response in post-ischemic injury. Cell Death and Disease, 1(11), [e96]. https://doi.org/10.1038/cddis.2010.76