The acetyltransferase HAT1 moderates the NF-κB response by regulating the transcription factor PLZF

Anthony J Sadler; Bandar A Suliman; Liang Yu; Xiangliang Yuan; Die Wang; Aaron T Irving; Soroush T Sarvestani; Ashish Banerjee; Ashley S Mansell; Jun-Ping Liu; Steve Gerondakis; Bryan R G Williams; Dakang Xu

doi:10.1038/ncomms7795

The acetyltransferase HAT1 moderates the NF-κB response by regulating the transcription factor PLZF

Nat Commun. 2015 Apr 13:6:6795. doi: 10.1038/ncomms7795.

Authors

Affiliations

¹ 1] Hudson Institute of Medical Research, 27-31 Wright Street, Clayton, Victoria 3168, Australia [2] Department of Molecular and Translational Science, Monash University, Melbourne, Victoria 3168, Australia.
² Hudson Institute of Medical Research, 27-31 Wright Street, Clayton, Victoria 3168, Australia.
³ Department of Laboratory Medicine, Xin Hua Hospital, Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China.
⁴ Institute of Ageing Research, Hangzhou Normal University School of Medicine, 1378 Wenyi Road West, Hangzhou, Zhejiang 311121, China.
⁵ Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University Clayton Campus, Wellington Road, Clayton, Victoria 3800, Australia.
⁶ 1] Hudson Institute of Medical Research, 27-31 Wright Street, Clayton, Victoria 3168, Australia [2] Department of Molecular and Translational Science, Monash University, Melbourne, Victoria 3168, Australia [3] Institute of Ageing Research, Hangzhou Normal University School of Medicine, 1378 Wenyi Road West, Hangzhou, Zhejiang 311121, China.

PMID: 25865065
DOI: 10.1038/ncomms7795

Abstract

To date, the activities of protein kinases have formed the core of our understanding of cell signal transduction. Comprehension of the extent of protein acetylation has raised expectations that this alternate post-transcriptional modification will be shown to rival phosphorylation in its importance in mediating cellular responses. However, limited instances have been identified. Here we show that signalling from Toll-like or TNF-α receptors triggers the calcium/calmodulin-dependent protein kinase (CaMK2) to activate histone acetyltransferase-1 (HAT1), which then acetylates the transcriptional regulator PLZF. Acetylation of PLZF promotes the assembly of a repressor complex incorporating HDAC3 and the NF-κB p50 subunit that limits the NF-κB response. Accordingly, diminishing the activity of CaMK2, the expression levels of PLZF or HAT1, or mutating key residues that are covalently modified in PLZF and HAT1, curtails control of the production of inflammatory cytokines. These results identify a central role for acetylation in controlling the inflammatory NF-κB transcriptional programme.

Publication types

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

MeSH terms

Acetylation
Animals
Calcium-Calmodulin-Dependent Protein Kinase Type 2 / genetics
Calcium-Calmodulin-Dependent Protein Kinase Type 2 / immunology
Histone Acetyltransferases / genetics*
Histone Acetyltransferases / immunology
Histone Deacetylases / genetics
Histone Deacetylases / immunology
Immunity, Innate
Inflammation / chemically induced
Inflammation / genetics
Inflammation / immunology
Inflammation / pathology
Kruppel-Like Transcription Factors / deficiency
Kruppel-Like Transcription Factors / genetics*
Kruppel-Like Transcription Factors / immunology
Lipopolysaccharides
Mice
Mice, Inbred C57BL
Mice, Knockout
Mutation
NF-kappa B / genetics*
NF-kappa B / immunology
Promyelocytic Leukemia Zinc Finger Protein
Protein Processing, Post-Translational*
Receptors, Tumor Necrosis Factor / genetics
Receptors, Tumor Necrosis Factor / immunology
Signal Transduction
Transcription, Genetic*

Substances

Kruppel-Like Transcription Factors
Lipopolysaccharides
NF-kappa B
Promyelocytic Leukemia Zinc Finger Protein
Receptors, Tumor Necrosis Factor
Zbtb16 protein, mouse
Histone Acetyltransferases
histone acetyltransferase type B complex
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Camk2a protein, mouse
Histone Deacetylases
histone deacetylase 3