| First Author | Cartwright TN | Year | 2018 |
| Journal | Biochim Biophys Acta Gene Regul Mech | Volume | 1861 |
| Issue | 10 | Pages | 962-970 |
| PubMed ID | 30496041 | Mgi Jnum | J:270465 |
| Mgi Id | MGI:6277750 | Doi | 10.1016/j.bbagrm.2018.09.001 |
| Citation | Cartwright TN, et al. (2018) HDAC1 interacts with the p50 NF-?B subunit via its nuclear localization sequence to constrain inflammatory gene expression. Biochim Biophys Acta Gene Regul Mech 1861(10):962-970 |
| abstractText | The NF-?B 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-?B subunit to activate inflammatory genes. However, p50 also forms homodimers which actively repress NF-?B-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-?B-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. |
