Essential Function for the Nuclear Protein Akirin2 in B Cell Activation and Humoral Immune Responses

Abstract

Akirin2, an evolutionarily conserved nuclear protein, is an important factor regulating inflammatory gene transcription in mammalian innate immune cells by bridging the NF-κB and SWI/SNF complexes. Although Akirin is critical for Drosophila immune responses, which totally rely on innate immunity, the mammalian NF-κB system is critical not only for the innate but also for the acquired immune system. Therefore, we investigated the role of mouse Akirin2 in acquired immune cells by ablating Akirin2 function in B lymphocytes. B cell–specific Akirin2-deficient (Cd19Cre/+Akirin2fl/fl) mice showed profound decrease in the splenic follicular (FO) and peritoneal B-1, but not splenic marginal zone (MZ), B cell numbers. However, both Akirin2-deficient FO and MZ B cells showed severe proliferation defect and are prone to undergo apoptosis in response to TLR ligands, CD40, and BCR stimulation. Furthermore, B cell cycling was defective in the absence of Akirin2 owing to impaired expression of genes encoding cyclin D and c-Myc. Additionally, Brg1 recruitment to the Myc and Ccnd2 promoter was severely impaired in Akirin2-deficient B cells. Cd19Cre/+Akirin2fl/fl mice showed impaired in vivo immune responses to T-dependent and -independent Ags. Collectively, these results demonstrate that Akirin2 is critical for the mitogen-induced B cell cycle progression and humoral immune responses by controlling the SWI/SNF complex, further emphasizing the significant function of Akirin2 not only in the innate, but also in adaptive immune cells.

A critical role for the nuclear protein Akirin2 in the formation of mammalian muscle in vivo

“…This is a finding reminiscent of our prior work on corticogenesis (Bosch et al, ), where we showed that massive cell death occurred in the telencephalon within 12 hr after Emx1‐Cre ‐mediated Aki2 deletion. In addition, other studies suggest that an important functional role for Aki2 occurs during rapid proliferation of cells in response to a stimulus (Komiya, Akiyama, Sakumoto, & Tashiro, ; Komiya et al, ; Tartey et al, ), consistent with our observations. In contrast, our knockdown experiments using shRNA against Aki2 in differentiating C2C12 cells did not cause any obvious cell death, and the presence of persistent tdTom‐positive cells in Aki2 SimKO mutants suggests that not all cells die when Aki2 is removed.…”

Akirin2 is essential for the formation of the cerebral cortex

“…It is interesting to note that Akirin2 knockout in B cells using CD19-Cre leads to reduced Cyclin D1 and Cyclin D2 mRNA expression [17]. Although typically associated with cell cycle progression, Cyclin D1 has also been reported to have a role in promoting neurogenesis in spinal cord that is independent of its cell cycle role [43].…”

“…In mammals, Akirin2 binds to BAF60 subunits, as well as NF-κB protein IκB-ζ, to mediate expression of proinflammatory genes in macrophages [16]. Additionally, in Akirin2 knockout B cells, Brg1 recruitment to several promoter targets is impaired [17]. The role of Akirin2 in coordinating gene expression via interactions with the BAF chromatin remodeling machinery is likely to be relevant to the cortical phenotypes we have observed here, as a spate of recent studies have uncovered a critical role for the BAF complex in neurogenesis.…”

“…This was subsequently shown to be conserved in mammals: Tartey et al found that mouse Akirin2 acts as a bridging protein between the NF-κB and BAF complexes, through an interaction between IκBζ and BAF60 [16]. Akirin2’s role in linking transcription factors and BAF chromatin remodeling machinery is critical for both innate and humoral immune responses in mice, via regulation of gene expression and B cell proliferation and survival [16, 17]. Interestingly, Akirin2 has also been implicated as an oncogene.…”

Impact of host genetic polymorphisms on vaccine induced antibody response

“…[26][27][28] Due to its complexity, the vaccine-induced immune response is a focus of on-going research and further processes involved in the humoral immune response have been reported. 29,30 Immunological network structure and robustness Basically, intercellular signaling processes of immune cells are orchestrated by cytokines, chemokines, and cell surface receptors, while intracellular signaling processes are conducted by various signaling pathways (e.g., TLR or Janus Kinase (JAK)/Signal transducer and activator of transcription (STAT) signaling pathway). Gene regulatory networks control both intra-and intercellular processes.…”