The Lysine Acetyltransferase GCN5 Is Required for iNKT Cell Development through EGR2 Acetylation

Cell Rep. 2017 Jul 18;20(3):600-612. doi: 10.1016/j.celrep.2017.06.065.

Abstract

The development of CD1d-restricted invariant natural killer T (iNKT) cells, a population that is critical for both innate and adaptive immunity, is regulated by multiple transcription factors, but the molecular mechanisms underlying how the transcriptional activation of these factors are regulated during iNKT development remain largely unknown. We found that the histone acetyltransferase general control non-derepressible 5 (GCN5) is essential for iNKT cell development during the maturation stage. GCN5 deficiency blocked iNKT cell development in a cell-intrinsic manner. At the molecular level, GCN5 is a specific lysine acetyltransferase of early growth responsive gene 2 (EGR2), a transcription factor required for iNKT cell development. GCN5-mediated acetylation positively regulated EGR2 transcriptional activity, and both genetic and pharmacological GCN5 suppression specifically inhibited the transcription of EGR2 target genes in iNKT cells, including Runx1, promyelocytic leukemia zinc finger protein (PLZF), interleukin (IL)-2Rb, and T-bet. Therefore, our study revealed GCN5-mediated EGR2 acetylation as a molecular mechanism that regulates iNKT development.

Keywords: EGR2; GCN5; acetylation; iNKT.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acetylation
  • Animals
  • Core Binding Factor Alpha 2 Subunit / genetics
  • Core Binding Factor Alpha 2 Subunit / immunology
  • Early Growth Response Protein 2 / genetics
  • Early Growth Response Protein 2 / immunology*
  • Interleukin-2 Receptor beta Subunit / genetics
  • Interleukin-2 Receptor beta Subunit / immunology
  • Mice
  • Mice, Transgenic
  • Natural Killer T-Cells / immunology*
  • Promyelocytic Leukemia Zinc Finger Protein / genetics
  • Promyelocytic Leukemia Zinc Finger Protein / immunology
  • T-Box Domain Proteins / genetics
  • T-Box Domain Proteins / immunology
  • T-bet Transcription Factor
  • p300-CBP Transcription Factors / genetics
  • p300-CBP Transcription Factors / immunology*

Substances

  • Core Binding Factor Alpha 2 Subunit
  • Early Growth Response Protein 2
  • Egr2 protein, mouse
  • Il2rb protein, mouse
  • Interleukin-2 Receptor beta Subunit
  • Promyelocytic Leukemia Zinc Finger Protein
  • Runx1 protein, mouse
  • T-Box Domain Proteins
  • T-bet Transcription Factor
  • Zbtb16 protein, mouse
  • p300-CBP Transcription Factors
  • p300-CBP-associated factor