MTA1 coregulator regulates LPS response via MyD88-dependent signaling.
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.
Pakala
Suresh B
SB
From the Department of Biochemistry and Molecular Biology, Institute of Coregulator Biology, George Washington University Medical Center, Washington, D. C. 20037.
Reddy
Sirigiri Divijendra Natha
SDN
From the Department of Biochemistry and Molecular Biology, Institute of Coregulator Biology, George Washington University Medical Center, Washington, D. C. 20037.
Bui-Nguyen
Tri M
TM
From the Department of Biochemistry and Molecular Biology, Institute of Coregulator Biology, George Washington University Medical Center, Washington, D. C. 20037.
Rangparia
Siddharth S
SS
From the Department of Biochemistry and Molecular Biology, Institute of Coregulator Biology, George Washington University Medical Center, Washington, D. C. 20037.
Bommana
Anitha
A
From the Department of Biochemistry and Molecular Biology, Institute of Coregulator Biology, George Washington University Medical Center, Washington, D. C. 20037.
Kumar
Rakesh
R
From the Department of Biochemistry and Molecular Biology, Institute of Coregulator Biology, George Washington University Medical Center, Washington, D. C. 20037. Electronic address: bcmrxk@gwumc.edu.
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins; D020218:Response Elements / Q000502:physiology; D012717:Sesquiterpenes / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D015534:Trans-Activators; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; C503336:Mta1 protein, mouse; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C498144:Rela protein, mouse; D012097:Repressor Proteins; D012717:Sesquiterpenes; D015534:Trans-Activators; D051996:Transcription Factor RelA; D014157:Transcription Factors; C002669:parthenolide