Brd4 modulates the innate immune response through Mnk2–eIF4E pathway-dependent translational control of IκBα

Abstract

Bromodomain-containing factor Brd4 has emerged as an important transcriptional regulator of NF-κB-dependent inflammatory gene expression. However, the in vivo physiological function of Brd4 in the inflammatory response remains poorly defined. We now demonstrate that mice deficient for Brd4 in myeloid-lineage cells are resistant to LPS-induced sepsis but are more susceptible to bacterial infection. Gene-expression microarray analysis of bone marrow-derived macrophages (BMDMs) reveals that deletion of Brd4 decreases the expression of a significant amount of LPS-induced inflammatory genes while reversing the expression of a small subset of LPS-suppressed genes, including MAP kinase-interacting serine/ threonine-protein kinase 2 (Mknk2). Brd4-deficient BMDMs display enhanced Mnk2 expression and the corresponding eukaryotic translation initiation factor 4E (eIF4E) activation after LPS stimulation, leading to an increased translation of IκBα mRNA in polysomes. The enhanced newly synthesized IκBα reduced the binding of NF-κB to the promoters of inflammatory genes, resulting in reduced inflammatory gene expression and cytokine production. By modulating the translation of IκBα via the Mnk2-eIF4E pathway, Brd4 provides an additional layer of control for NF-κB-dependent inflammatory gene expression and inflammatory response.T he inducible transcription factor NF-κB plays a key role in regulating the inflammatory and immune responses in mammals (1, 2). The prototypical NF-κB complex, the heterodimer of p50 and RelA, is sequestered in the cytoplasm by its assembly with its inhibitor IκBα (1, 2). Upon stimulation, IκB kinase complex is activated and phosphorylates IκBα, leading to the degradation of IκBα, the nuclear translocation of NF-κB complex, and the activation of NF-κB target genes (1-3). Importantly, one of NF-κB target genes is its inhibitor, IκBα. The resynthesized IκBα enters the nucleus, where it removes the NF-κB from the DNA and terminates activated NF-κB (1, 2, 4). The resynthesis of IκBα therefore creates a negative feedback regulation of NF-κB signaling, preventing sustained NF-κB activation and prolonged inflammatory response.In addition to the negative feedback regulation from resynthesized IκBα, the NF-κB-mediated inflammatory response is subjected to many layers of regulation, including transcriptional, translational, and posttranslational regulation (5-8). Recent studies demonstrate that selective translational control of gene expression plays an important regulatory role in the inflammatory response (7, 9). The eukaryotic translation initiation factor eIF4E has been shown to be the node of the translational control of immune response via the mTOR signaling pathway or the MAPK-Mnk1-Mnk2-eIF4E pathway (9). Upon LPS stimulation, eIF4E can be activated via its phosphorylation at S209 by Mnk1/2 (10). The phosphorylated eIF4E then activates the translation of mRNA of inflammatory genes, including IRF8 (11, 12). Interestingly, the translation of IκBα is also regulated by the phosphorylation and activation of e...

BRD4 directs hematopoietic stem cell development and modulates macrophage inflammatory responses

“…First, BRD4-independent genes still bound Pol II without BRD4, thus retaining the capacity for transcriptional initiation and elongation. Thus, NF-jB expression and nuclear residence were not altered in KO macrophages (Bao et al, 2017). Our data may point to a compensatory role for BRD2 and BRD3, given slightly elevated expression in Brd4 KO cells.…”

“…This compensatory activity may be attributed at least partly to BRD2 and BRD3. Thus, NF-jB expression and nuclear residence were not altered in KO macrophages (Bao et al, 2017). Irrespective of the mechanisms, increased NF-jB binding in KO macrophages would provide an added layer of compensation, allowing macrophages to retain their most important role, to mount a timely inflammatory response.…”

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“…I-BET inhibits the expression of key inflammatory genes in activated macrophages and primary human monocytes [63,64]. Deletion of BRD4 promotes IκBα transcription and influences LPS-induced inflammatory gene expression and cytokine production in bone marrowderived macrophages [65]. In addition, BRD4 binds the IFN-β promoter and facilitates IFN-β expression [66].…”