Induction of TLR4-target genes entails calcium/calmodulin-dependent regulation of chromatin remodeling.
Upon toll-like receptor 4 (TLR4) signaling in macrophages, the mammalian Swi/Snf-like BAF chromatin remodeling complex is recruited to many TLR4 target genes where it remodels their chromatin to promote transcription. Here, we show that, surprisingly, recruitment is not sufficient for chromatin remodeling; a second event, dependent on calcium/calmodulin (CaM), is additionally required. Calcium/CaM directly binds the HMG domain of the BAF57 subunit within the BAF complex. Calcium/CaM antagonists, including a CaM-binding peptide derived from BAF57, abolish BAF-dependent remodeling and gene expression without compromising BAF recruitment. BAF57 RNAi and BAF57 dominant negative mutants defective in CaM binding similarly impair the induction of BAF target genes. Our data implicate calcium/CaM in TLR4 signaling, and reveal a previously undescribed, recruitment-independent mode of regulation of the BAF complex that is probably achieved through a direct CaM-BAF interaction.
Lai
Dazhi
D
Department of Immunobiology, Yale University Medical School, New Haven, CT 06520, USA.
Wan
Mimi
M
Wu
Jie
J
Preston-Hurlburt
Paula
P
Kushwaha
Ritu
R
Grundström
Thomas
T
Imbalzano
Anthony N
AN
Chi
Tian
T
D002118:Calcium / Q000378:metabolism*; D002147:Calmodulin / Q000378:metabolism*; D042002:Chromatin Assembly and Disassembly; D002868:Chromosomal Proteins, Non-Histone / Q000737:chemistry / Q000378:metabolism; D004265:DNA Helicases / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008264:Macrophages / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism
D002147:Calmodulin; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C504738:SMARCE1 protein, human; D051197:Toll-Like Receptor 4; D014157:Transcription Factors; C084108:SMARCA4 protein, human; D004265:DNA Helicases; D002118:Calcium