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Related Experiment Videos

NF-kappaB RelA phosphorylation regulates RelA acetylation.

Lin-Feng Chen1, Samuel A Williams, Yajun Mu

  • 1Gladstone Institute of Virology and Immunology, 1650 Owens St., San Francisco, CA 94158, USA. lchen@gladstone.ucsf.edu

Molecular and Cellular Biology
|September 2, 2005
PubMed
Summary

Prior phosphorylation of RelA at serine 276 or 536 enhances its acetylation at lysine 310. This dual modification boosts NF-kappaB

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Area of Science:

  • Molecular Biology
  • Cellular Signaling
  • Immunology

Background:

  • Nuclear factor-kappaB (NF-kappaB) heterodimers, specifically p50/RelA, play crucial roles in cellular functions.
  • Posttranslational modifications, including phosphorylation and acetylation of the RelA subunit, are known regulators of NF-kappaB activity.
  • The precise regulation of RelA acetylation, particularly at lysine 310, and its relationship with phosphorylation remained unclear.

Purpose of the Study:

  • To investigate the regulatory mechanisms governing RelA acetylation at lysine 310.
  • To determine the interplay between RelA phosphorylation at serine 276/536 and its subsequent acetylation.
  • To elucidate the functional consequences of combined phosphorylation and acetylation on NF-kappaB transcriptional activity.

Main Methods:

Related Experiment Videos

  • Utilized antibodies specific for acetylated lysine 310 RelA to detect and quantify modification.
  • Performed in vitro and in vivo acetylation assays using p300.
  • Employed catalytically inactive kinase mutants (PKA/MSK1, IKK1/IKK2) to assess the role of phosphorylation.
  • Generated RelA-deficient murine embryonic fibroblasts reconstituted with serine-to-alanine mutants (RelA S276A, RelA S536A).

Main Results:

  • Demonstrated p300-mediated acetylation of RelA at lysine 310 in response to tumor necrosis factor alpha (TNF-alpha) stimulation.
  • Showed that prior phosphorylation of RelA at serine 276 or 536 significantly inhibited lysine 310 acetylation.
  • Found that phosphorylation at serine 276/536 promotes RelA assembly with p300, thereby enhancing lysine 310 acetylation.
  • Observed reduced TNF-alpha-induced lysine 310 acetylation and E-selectin gene expression in cells expressing RelA S276A or S536A mutants.

Conclusions:

  • RelA acetylation at lysine 310 is dynamically regulated by preceding phosphorylation events at serine 276 and serine 536.
  • Phosphorylation enhances the recruitment of p300, facilitating subsequent acetylation.
  • The combined phosphorylation and acetylation of RelA significantly potentiate its transcriptional activity, particularly in response to inflammatory stimuli like TNF-alpha.