title: MTA1 coregulation of transglutaminase 2 expression and function during inflammatory response.
abstract: Although both metastatic tumor antigen 1 (MTA1), a master chromatin modifier, and transglutaminase 2 (TG2), a multifunctional enzyme, are known to be activated during inflammation, it remains unknown whether these molecules regulate inflammatory response in a coordinated manner. Here we investigated the role of MTA1 in the regulation of TG2 expression in bacterial lipopolysaccharide (LPS)-stimulated mammalian cells. While studying the impact of MTA1 status on global gene expression, we unexpectedly discovered that MTA1 depletion impairs the basal as well as the LPS-induced expression of TG2 in multiple experimental systems. We found that TG2 is a chromatin target of MTA1 and of NF-κB signaling in LPS-stimulated cells. In addition, LPS-mediated stimulation of TG2 expression is accompanied by the enhanced recruitment of MTA1, p65RelA, and RNA polymerase II to the NF-κB consensus sites in the TG2 promoter. Interestingly, both the recruitment of p65 and TG2 expression are effectively blocked by a pharmacological inhibitor of the NF-κB pathway. These findings reveal an obligatory coregulatory role of MTA1 in the regulation of TG2 expression and of the MTA1-TG2 pathway, at least in part, in LPS modulation of the NF-κB signaling in stimulated macrophages.
authors.affiliation: Department of Biochemistry and Molecular Biology and Institute of Coregulator Biology, The George Washington University Medical Center, Washington, DC 20037, USA.
authors.forename: Krishna Sumanth
authors.initials: KS
authors.lastname: Ghanta
authors.forename: Suresh B
authors.initials: SB
authors.lastname: Pakala
authors.forename: Sirigiri Divijendra Natha
authors.initials: SD
authors.lastname: Reddy
authors.forename: Da-Qiang
authors.initials: DQ
authors.lastname: Li
authors.forename: Sujit S
authors.initials: SS
authors.lastname: Nair
authors.forename: Rakesh
authors.initials: R
authors.lastname: Kumar
mesh_terms: D000818:Animals; D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000276:immunology; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000503:physiopathology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D012097:Repressor Proteins / Q000378:metabolism; D015534:Trans-Activators; D014157:Transcription Factors / Q000378:metabolism*; D011503:Transglutaminases / Q000235:genetics / Q000378:metabolism*
chemical_list: D008070:Lipopolysaccharides; C089320:MTA1 protein, human; C503336:Mta1 protein, mouse; D016328:NF-kappa B; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D006655:Histone Deacetylases; D019204:GTP-Binding Proteins