Phosphorylation of serine 276 is essential for p65 NF-κB subunit-dependent cellular responses

Tatsuma Okazaki, Sachiko Sakon, Tomonari Sasazuki, Hiroaki Sakurai, Takahiro Doi, Hideo Yagita, Ko Okumura, Hiroyasu Nakano

Research output: Contribution to journalArticlepeer-review

134 Citations (Scopus)

Abstract

Phosphorylation of several serine residues especially in the transactivation (TA) domain of p65 NF-κB subunit has been suggested to be important for its transcriptional activity. However, the responsible phosphorylation site of p65 remains controversial. To investigate the biological significance of phosphorylation and to determine the critical phosphorylation sites of p65, we reconstituted murine embryonic fibroblasts (MEFs) from p65-/- mice with various serine to alanine (SA)-substituted mutants of p65. Unexpectedly, mutants in the TA domain, including S529A, S536A, and S529A/S536A, completely rescued the defect of p65-/- MEFs as assessed by tumor necrosis factor (TNF)- or interleukin-1 (IL-1)-induced IL-6 production and protection from TNF-induced cell death. On the other hand, S276A mutant had an impaired ability to rescue these responses. Moreover, TNF-induced phosphorylation of p65 was severely impaired in S276A mutant, indicating that S276 is the major phosphorylation site of p65 and its phosphorylation is essential for p65-dependent cellular responses.

Original languageEnglish
Pages (from-to)807-812
Number of pages6
JournalBiochemical and biophysical research communications
Volume300
Issue number4
DOIs
Publication statusPublished - 2003 Jan 24
Externally publishedYes

Keywords

  • Cell death
  • NF-κB
  • Phosphorylation
  • TNF
  • Transcriptional activity
  • p65

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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