Tyrell Cartwright paper in BBA GRM

Tyrell Cartwright leads NFRG paper in BBA Gene Regulatory Mechanisms

A new paper resulting from a collective work among many NFRG staff* and led by Tyrell Cartwright has just been published in BBA Gene Regulatory Mechanisms. This new paper is entitled:

HDAC1 interacts with the p50 NF-κB subunit via its nuclear localization sequence to constrain inflammatory gene expression

 

Abstract

The NF-κB p50 subunit is an important regulator of inflammation, with recent experimental evidence to support it also having a tumor suppressor role. Classically, p50 functions in heterodimeric form with the RelA (p65) NF-κB subunit to activate inflammatory genes. However, p50 also forms homodimers which actively repress NF-κB-dependent inflammatory gene expression and exert an important brake on the inflammatory process. This repressive activity of p50:p50 is thought to be in part mediated by an interaction with the epigenetic repressor protein Histone Deacetylase 1 (HDAC1). However, neither the interaction of p50 with HDAC1 nor the requirement of HDAC1 for the repressive activities of p50 has been well defined. Here we employed in silico prediction with in vitro assays to map sites of interaction of HDAC1 on the p50 protein. Directed mutagenesis of one such region resulted in almost complete loss of HDAC1 binding to p50. Transfected mutant p50 protein lacking the putative HDAC1 docking motif resulted in enhanced cytokine and chemokine expression when compared with cells expressing a transfected wild type p50. In addition, expression of this mutant p50 was associated with enhanced chemoattraction of neutrophils and acetylation of known inflammatory genes demonstrating the likely importance of the p50:HDAC1 interaction for controlling inflammation. These new insights provide an advance on current knowledge of the mechanisms by which NF-κB-dependent gene transcription are regulated and highlight the potential for manipulation of p50:HDAC1 interactions to bring about experimental modulation of chronic inflammation and pathologies associated with dysregulated neutrophil accumulation and activation.

 

Highlights

  • We confirm that HDAC1 interacts with p50 in both primary and transformed cells;
  • We have identified a site of interaction between HDAC1 and p50 located at the p50 C-terminal nuclear localization signal;
  • Mutation of this site results in a complete loss of p50:HDAC1 interaction yet did not affect nuclear translocation;
  • This mutation also leads to increased histone acetylation and elevated cytokine and chemokine expression.

Please, click HERE to read and download the full article

Tyrell_Cartwright

 

* Julie C. Worrell, Letizia Marchetti, Amber Knox, Jelena Mann, Derek Mann, Caroline Wilson

Author Jeremy Domis

Last modified: Tue, 25 Sep 2018 09:58:22 BST