Arid5a, an RNA-Binding Protein in Immune Regulation: RNA Stability, Inflammation, and Autoimmunity

Toll-like receptor (TLR)4-induced nuclear factor (NF)-κB and mitogen-activated protein kinase (MAPK) signaling regulates Arid5a from synthesis to degradation. Recent discoveries have suggested that Arid5a, a dynamic protein, translocates to the cytoplasm from the nucleus under inflammatory conditions and performs dual functions in mRNA stabilization and transcriptional regulation. Arid5a stabilizes a variety of inflammatory mRNAs, such as Il6, Stat3, Ox40, Tbx21, and interleukin (IL)-17-target genes. Arid5a plays a role in the fate decisions of naïve murine CD4+ T cells, inducing these cells to differentiate into inflammatory CD4+ T cells, especially T helper (Th)17 cells, by stabilizing Stat3 mRNA. Arid5a-/- mice exhibit resistance to lipopolysaccharide-induced endotoxic shock, bleomycin-induced lung injury, and experimental autoimmune encephalomyelitis. They also show reduced concentrations of proinflammatory cytokines relative to wild type mice. A new and exciting therapeutic opportunity for putatively treating certain human inflammatory and autoimmune diseases may be to strategically block ARID5A; this might require in part, identifying the occurrence of ARID5A translocation as a possible underlying cause or contributing factor in certain diseases associated with aberrant cytokine expression and increased mRNA stability of inflammatory mediators. To effectively translate the knowledge of Arid5a biology into potential new therapeutics, precise definitions of the cellular players, molecular mediators, receptors, and signaling pathways engaged during Arid5a-mediated inflammation are necessary. AT-rich interactive domain 5A (ARID5A/Arid5a) is a known cofactor of transcription factors (TFs) that contributes to cell growth and differentiation. It has recently been recognized for its unique function in the stabilization of mRNA, which is associated with inflammatory autoimmune diseases. Studies have revolutionized our understanding of the post-transcriptional regulation of inflammatory genes by revealing the fundamental events underpinning novel functions and activities of Arid5a. We review current research on Arid5a, which has focused our attention towards the therapeutic potential of this factor in the putative treatment of inflammatory and autoimmune disorders, including experimental autoimmune encephalomyelitis and sepsis in mice. AT-rich interactive domain 5A (ARID5A/Arid5a) is a known cofactor of transcription factors (TFs) that contributes to cell growth and differentiation. It has recently been recognized for its unique function in the stabilization of mRNA, which is associated with inflammatory autoimmune diseases. Studies have revolutionized our understanding of the post-transcriptional regulation of inflammatory genes by revealing the fundamental events underpinning novel functions and activities of Arid5a. We review current research on Arid5a, which has focused our attention towards the therapeutic potential of this factor in the putative treatment of inflammatory and autoimmune disorders, including experimental autoimmune encephalomyelitis and sepsis in mice. section of mRNA that immediately follows the translation termination codon and contains gene regulatory regions. disorder of acute inflammation that causes disruption of the lung endothelial and epithelial barriers. type of respiratory failure characterized by rapid onset of widespread inflammation in the lungs. chemotherapeutic agent used to induce lung injury in animal models and for the treatment of several types of malignancy. fluid that is squirted into a small part of the lung while passing a bronchoscope through the mouth or nose into the lungs. group of lymphoproliferative disorders characterized by lymph node enlargement. antihistaminic and antipsychotic drug primarily used to treat psychotic disorders such as schizophrenia. also known as exportin1; eukaryotic protein mediating the nuclear export of proteins, rRNA, small nuclear (sn)RNA, and some mRNAs. system for the transport of macromolecules between the cytoplasm and the nucleus. overproduction of immune cells that release enormous amounts of cytokines. condition characterized by a severe, generalized inflammatory response induced by bloodstream infection with Gram-negative bacteria. commonly used experimental model for multiple sclerosis – a T helper cell-mediated autoimmune disease. subset of CD4+ T cells providing help to B cells to allow formation of long-lived antibody responses. membrane component of Gram-negative bacteria with strong proinflammatory properties. an important phenomenon used by cells to control gene expression and to adjust the level of protein synthesis. protein complex that controls transcription of DNA, cytokine production, and cell survival. mixture of oxidized phospholipids that inhibits signaling induced by TLR2 and TLR4. control mechanism for gene expression at the RNA level between the transcription and translation of a gene. reactive chemical species containing oxygen that are formed as a natural byproduct of oxygen metabolism. autoimmune disease resulting in joint inflammation and damage to the surrounding bone and cartilage. proteins binding to double- or single-stranded RNA in cells and participating in the formation of ribonucleoprotein complexes. the body’s overwhelming and life-threatening response to infection, which can lead to tissue damage, organ failure, and death. transmembrane protein of the innate immune system. Its activation leads to an intracellular signaling pathway involving NF-κB and inflammatory cytokine production. proinflammatory T cell subset characterized by high production of IL-17. characterized by IFN-γ production; they promote macrophage activation and the clearance of intracellular bacteria.