Arid5a Regulation and the Roles of Arid5a in the Inflammatory Response and Disease

Figures

• 

  Figure 1. Regulatory pathways for Arid5a under TLR4 signaling. The schematic diagram shows the gene expression of Arid5a (black arrow) induced by the TLR4/IKK/NF-κB and IL-6/STAT3 signaling pathways. LPS-bound TLR4 leads to the release of NF-κB from the IKK complex and activates Arid5a and other inflammatory genes, such as Il-6. Arid5a then stabilizes Il-6 mRNA (blue arrow), increasing the production of IL-6. Another pathway shows the posttranscriptional regulation of Arid5a mRNA (blue arrow), in which TLR4 signaling stimulates MKP-1, which in turn directs AUF-1 to translocate to the cytoplasm. Cytoplasmic AUF-1 binds to AU-rich elements present in the 3′UTR of the Arid5a mRNA transcript, which results in destabilization of the Arid5a mRNA (blue arrow). The LPS/TLR4 pathway activates p38, leading to phosphorylation of the Arid5a protein at serine residues 253, 433, and 458. This phosphorylation is associated with the ubiquitination of Arid5a at lysines 80 and 89 by WWP1 E3 ligase and subsequent degradation of the protein.

• 

  Figure 2. Contribution of Arid5a in IL-6 production and disease. The innate immune response is generated by pathogen-associated molecular patterns, which are recognized by pathogen recognition receptors and lead to expression of proinflammatory mediators. For example, toll-like receptor 4 recognizes lipopolysaccharide and activates the IKK/NF-κB signaling pathway. The IKK complex phosphorylates Regnase-1 and also promotes transcription of Il-6 and Arid5a. Regnase-1 binds to the Il-6 mRNA and degrades it. In the nucleus, Arid5a binds to genes encoding transcription factors, such as Ppar-γ2, to inhibit their expression. Furthermore, Arid5a is shuttled to the cytoplasm under inflammatory conditions where it interferes with the destabilizing effect of Regnase-1. Arid5a is involved in Il-6 mRNA stabilization, and the resulting increase in IL-6 production is associated with inflammation and autoimmune diseases.

• 

  Figure 3. Arid5a translocation and association with adipogenesis and obesity. (A) In the resting stage, Arid5a usually resides in the nucleus. Arid5a is imported via an importin-α/β1 pathway. UPF1 shuttles between the nucleus and the cytoplasm. During inflammation, toll-like receptor 4 signaling is activated by lipopolysaccharide, and Il-6 expression is induced by NF-κB. Arid5a interacts with the Il-6 mRNA, and Arid5a is subsequently exported to the cytoplasm via the CRM1 pathway with UPF1. (B) Arid5a and Ppar-γ2 in adipogenic homeostasis. Cebp activates Ppar-γ2, and both are involved in adipogenesis. Immune cells, such as macrophages and T cells, infiltrate adipose tissues and provide a framework to regulate energy homeostasis. In adipose tissue, these cells secrete cytokines, such as IL-6 and IL-17, which induce Arid5a. Arid5a further represses Ppar-γ2 transcription in fibroblasts, thereby inhibiting adipocyte development and inhibiting adipogenesis and obesity.