Chromatin Remodeling and Transcriptional Control in Innate Immunity: Emergence of Akirin2 as a Novel Player

Transcriptional regulation of inflammatory gene expression has been at the forefront of studies of innate immunity and is coordinately regulated by transcription factors, including NF-κB, and chromatin modifiers. The growing evidence for involvement of chromatin in the regulation of gene expression in innate immune cells, has uncovered an evolutionarily conserved role of microbial sensing and chromatin remodeling. Toll-like receptors and RIG-I-like receptors trigger these signaling pathways leading to transcriptional expression of a set of genes involved in inflammation. Tightly regulated control of this gene expression is a paramount, and often foremost, goal of most biological endeavors. In this review, we will discuss the recent progress about the molecular mechanisms governing control of pro-inflammatory gene expression by an evolutionarily conserved novel nuclear protein Akirin2 in macrophages and its emergence as an essential link between NF-κB and chromatin remodelers for transcriptional regulation

Akirin2 is critical for inducing inflammatory genes by bridging IκB-ζ and the SWI/SNF complex.

Transcription of inflammatory genes in innate immune cells is coordinately regulated by transcription factors, including NF-κB, and chromatin modifiers. However, it remains unclear how microbial sensing initiates chromatin remodeling. Here, we show that Akirin2, an evolutionarily conserved nuclear protein, bridges NF-κB and the chromatin remodeling SWI/SNF complex by interacting with BRG1-Associated Factor 60 (BAF60) proteins as well as IκB-ζ, which forms a complex with the NF-κB p50 subunit. These interactions are essential for Toll-like receptor-, RIG-I-, and Listeria-mediated expression of proinflammatory genes including Il6 and Il12b in macrophages. Consistently, effective clearance of Listeria infection required Akirin2. Furthermore, Akirin2 and IκB-ζ recruitment to the Il6 promoter depend upon the presence of IκB-ζ and Akirin2, respectively, for regulation of chromatin remodeling. BAF60 proteins were also essential for the induction of Il6 in response to LPS stimulation. Collectively, the IκB-ζ-Akirin2-BAF60 complex physically links the NF-κB and SWI/SNF complexes in innate immune cell activation. By recruiting SWI/SNF chromatin remodellers to IκB-ζ, transcriptional coactivator for NF-κB, the conserved nuclear protein Akirin2 stimulates pro-inflammatory gene promoters in mouse macrophages during innate immune responses to viral or bacterial infection

Regnase-1 and Roquin Regulate a Common Element in Inflammatory mRNAs by Spatiotemporally Distinct Mechanisms.

炎症がRNA分解により制御されるメカニズムを解明 -二つのブレーキが炎症を巧妙にストップする-. 京都大学プレスリリース. 2015-05-22.Regnase-1 and Roquin are RNA binding proteins essential for degradation of inflammation-related mRNAs and maintenance of immune homeostasis. However, their mechanistic relationship has yet to be clarified. Here, we show that, although Regnase-1 and Roquin regulate an overlapping set of mRNAs via a common stem-loop structure, they function in distinct subcellular locations: ribosome/endoplasmic reticulum and processing-body/stress granules, respectively. Moreover, Regnase-1 specifically cleaves and degrades translationally active mRNAs and requires the helicase activity of UPF1, similar to the decay mechanisms of nonsense mRNAs. In contrast, Roquin controls translationally inactive mRNAs, independent of UPF1. Defects in both Regnase-1 and Roquin lead to large increases in their target mRNAs, although Regnase-1 tends to control the early phase of inflammation when mRNAs are more actively translated. Our findings reveal that differential regulation of mRNAs by Regnase-1 and Roquin depends on their translation status and enables elaborate control of inflammation