MTA1 Coregulator Regulates LPS Response via MyD88-dependent Signaling

• Published in: The Journal of biological chemistry 2010-10, Vol.285 (43), p.32787-32792
• Main Authors: Pakala, Suresh B., Reddy, Sirigiri Divijendra Natha, Bui-Nguyen, Tri M., Rangparia, Siddharth S., Bommana, Anitha, Kumar, Rakesh
• Format: Article
• Language: English
• Subjects: Animals; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Cell Line; Chromatin Immunoprecipitation (ChIP); Coregulator; Cytokine Induction; Cytokines - biosynthesis; Cytokines - genetics; Gene Expression Regulation - drug effects; Gene Expression Regulation - genetics; Gene Regulation; Inflammation Mediators - metabolism; Lipopolysaccharide (LPS); Lipopolysaccharides - pharmacology; Macrophage; Macrophages, Peritoneal - cytology; Macrophages, Peritoneal - metabolism; Mice; Molecular Bases of Disease; MTA1; MyD88; Myeloid Differentiation Factor 88 - genetics; Myeloid Differentiation Factor 88 - metabolism; Promoters; Repressor Proteins; Response Elements - physiology; Sesquiterpenes - pharmacology; Signal Transduction - drug effects; Signal Transduction - genetics; Trans-Activators; Transcription Factor RelA - genetics; Transcription Factor RelA - metabolism; Transcription Factors - genetics; Transcription Factors - metabolism; Transcription Repressor; Transcription, Genetic - drug effects; Transcription, Genetic - genetics
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M110.151340

Although metastasis tumor antigen 1 (MTA1) contributes to the responsiveness of macrophages to LPS, the underlying mechanism remains unknown. Here, we investigated the role of MTA1 in the regulation of expression and function of MyD88, a proximal component of NF-κB signaling. We discovered that MTA1 targets MyD88 and that MyD88 is a NF-κB-responsive gene in LPS-stimulated macrophages. We found that MTA1 is required for MyD88-dependent stimulation of NF-κB signaling and expression of proinflammatory cytokines such as IL-1β, MIP2, and TNF-α as MTA1 depletion leads to a substantial reduction in the expression of NF-κB target genes. In addition, LPS-mediated stimulation of MyD88 transcription was accompanied by an enhanced recruitment of MTA1, RNA polymerase II, and p65RelA complex to the NF-κB consensus sites in the MyD88 promoter. Interestingly, the recruitment of both MTA1 and MyD88 expression is effectively blocked by NF-κB inhibitor parthenolide. Selective knockdown of MyD88 by a dominant negative mutant of MyD88 or selective siRNA also impairs the ability of LPS to stimulate the NF-κB target genes. These findings reveal an inherent coregulatory role of MTA1 upon the expression of MyD88 and suggest that MTA1 regulation of MyD88 may constitute at least one of the mechanisms by which MTA1 stimulates LPS-induced NF-κB signaling in stimulated macrophages.