Akirin specifies NF ‐κB selectivity of Drosophila innate immune response via chromatin remodeling

Abstract

The network of NF-κB-dependent transcription that activates both pro- and anti-inflammatory genes in mammals is still unclear. As NF-κB factors are evolutionarily conserved, we used Drosophila to understand this network. The NF-κB transcription factor Relish activates effector gene expression following Gram-negative bacterial immune challenge. Here, we show, using a genome-wide approach, that the conserved nuclear protein Akirin is a NF-κB co-factor required for the activation of a subset of Relish-dependent genes correlating with the presence of H3K4ac epigenetic marks. A large-scale unbiased proteomic analysis revealed that Akirin orchestrates NF-κB transcriptional selectivity through the recruitment of the Osa-containing-SWI/SNF-like Brahma complex (BAP). Immune challenge in Drosophila shows that Akirin is required for the transcription of a subset of effector genes, but dispensable for the transcription of genes that are negative regulators of the innate immune response. Therefore, Akirins act as molecular selectors specifying the choice between subsets of NF-κB target genes. The discovery of this mechanism, conserved in mammals, paves the way for the establishment of more specific and less toxic anti-inflammatory drugs targeting pro-inflammatory genes.

Functional screening of mammalian mechanosensitive genes using Drosophila RNAi library– Smarcd3/Bap60 is a mechanosensitive pro-inflammatory gene

“…Recently, Bonnay et al showed that Drosophila Bap60 interacts with Akirin upon immune challenge, and Bap60-Akirin complex is required for the induction of a subset of IMD target genes, indicating that Bap60 acts as a positive regulator for IMD-pathway42, and is consistent with our result obtained using the inducible Bap60 RNAi flies (Fig. 2D).…”

The immune signaling pathways of Manduca sexta

“…Another deubiquitinase, CYLD (for Cylindromatosis), modulates the IKK complex to control Relish phosphorylation (Tsichritzis et al, 2007). POSH controls the complex of TAK1 and TAB2; an SCF complex of S kp1, C ullin and F -box protein regulates the phosphorylated Relish-N; Akirin and Relish-N co-regulate some target genes of the Imd pathway (Tsuda et al, 2005; Cardozo and Pagano, 2004; Bonnay et al, 2014). …”

Evolution of akirin family in gene and genome levels and coexpressed patterns among family members and rel gene in croaker

“…Meanwhile, akirins participate in regulating gene expressions in numerous physiological processes, including the innate immune responses of mammalians and insects (Goto et al, 2008;Tartey et al, 2014), metazoan myogenesis (Marshall et al, 2008;Salerno et al, 2009), mammalian carcinogenesis (Komiya et al, 2008), insect reproduction, and arthropod growth (Almazán et al, 2005;de la Fuente et al, 2006de la Fuente et al, , 2008. Furthermore, the study demonstrated that akirins are required to activate a subset of Relish-dependent genes (Bonnay et al, 2014). Akirins acted in concert with relish (rel) protein in the NFkB dependent signaling pathway, which induces the expression of a subset of downstream pathway elements (e.g., LEAP-1 and LEAP-2) (Goto et al, 2008;Hou et al, 2013;Xue et al, 2014).…”