Regulation of NF-kappaB circuitry by a component of the nucleosome remodeling and deacetylase complex controls inflammatory response homeostasis.
The MTA1 coregulator (metastatic tumor antigen 1), a component of the nucleosome remodeling and deacetylase (NuRD) complex, has been intimately linked with human cancer, but its role in inflammatory responses remains unknown. Here, we discovered that MTA1 is a target of inflammation, and stimulation of macrophages with Escherichia coli lipopolysaccharide (LPS) stimulates MTA1 transcription via the NF-kappaB pathway. Unexpectedly, we found that MTA1 depletion in LPS-stimulated macrophages impairs NF-kappaB signaling and expression of inflammatory molecules. MTA1 itself acts as a transcriptional coactivator of inflammatory cytokines in LPS-stimulated macrophages, and in contrast, it acts as a corepressor in resting primary macrophages as its depletion induced cytokine expression. LPS stimulates S-nitrosylation of histone deacetylase 2 (HDAC2) and interferes with its binding to MTA1, which, in turn, resulted in the loss of corepressor behavior of MTA1.HDAC complex in activated macrophages. Consequently, the net levels of inflammatory cytokines in LPS-stimulated macrophages from MTA1(-/-) mice were high compared with wild-type mice. Accordingly, MTA1(-/-) mice were much more susceptible than control mice to septic shock induced by LPS, revealing that MTA1 protects mice from deregulated host inflammatory response. These findings reveal a previously unrecognized, critical homeostatic role of MTA1, both as a target and as a component of the NF-kappaB circuitry, in the regulation of inflammatory responses.
Department of Biochemistry and Molecular Biology, The George Washington University Medical Center, Washington, D.C. 20037, USA.
Suresh B
SB
Pakala
Tri M
TM
Bui-Nguyen
Sirigiri Divijendra Natha
SD
Reddy
Da-Qiang
DQ
Li
Shaohua
S
Peng
Suresh K
SK
Rayala
Richard R
RR
Behringer
Rakesh
R
Kumar
D000818:Animals; D003001:Cloning, Molecular; D004926:Escherichia coli / Q000378:metabolism; D005786:Gene Expression Regulation; D015971:Gene Expression Regulation, Enzymologic; D056464:Histone Deacetylase 2 / Q000378:metabolism; D006706:Homeostasis; D007249:Inflammation; D008070:Lipopolysaccharides / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism*; D009707:Nucleosomes / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors / Q000378:metabolism
D008070:Lipopolysaccharides; C503336:Mta1 protein, mouse; D016328:NF-kappa B; D009707:Nucleosomes; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D056464:Histone Deacetylase 2