The subcellular dynamics of RNA stabilizing molecule in response to inflammation~Inflammation is regulated by the balance of accelerator and brake~

Points･Arid5a*1) contributes to augmentation of inflammatory cytokine serum levels in vivo.
･Arid5a translocates to the cytoplasm from the nucleus in response to inflammation.
･The nucleocytoplasmic translocation of Arid5a is regulated by importin-α/β1 and CRM1.
･CRM1 Inhibitor, Leptomycin B, inhibited the nuclear export of Arid5a and IL-6*2) production after LPS stimulation.

Summary
Mitsuru Higa, Tadamitsu Kishimoto, and theirresearch group revealed the regulatory mechanismof subcellular localization of Arid5a in response toinflammation. It has been known that an inflammatory
accelerator, Arid5a, is localized in the nucleus, andan inflammatory brake, Regnase-1*3), is localized in
the cytoplasm. In this study, they showed that 1)
Arid5a translocates to the cytoplasm from thenucleus in response to inflammation, 2) bimax, which
inhibit cNLS-dependent nuclear import via highaffinity interactions with NLS-binding sites ofimportin-α, inhibits the nuclear import of Arid5a, 3) CRM1 inhibitor, Leptomycin B, inhibits the nuclear export of Arid5a
after LPS stimulation.

Background
Macrophages produce inflammatory cytokines to active other immune cells and to exclude pathogens. However, overor chronic inflammation causes diseases including a septic shock or autoimmunity. Therefore, the group has beenstudied the control mechanism of inflammation, especially focusing on the posttranscriptional regulation of the Il6mRNA by Arid5a and Regnase-1. Previous study showed that Arid5a binds to Il6 mRNA 3′UTR to inhibit Regnase-1mediatedRNA decay. Additionally, Arid5a deficient mice showed down-regulated inflammatory cytokine production, resistance toseptic shock, and bleomycin-induced lung injury. Although Arid5a is known to play an important role in immune
regulation, whether and how Arid5a subcellular localization impacts immune regulation has remained unclear.

Significance of the findings
The group showed that Arid5a translocates from the nucleus to the cytoplasm after LPS stimulation. Since theinhibition of Arid5a nuclear export causes the significant suppression of IL-6 production, further understanding ofArid5a dynamics may lead to novel therapeutic strategies of septic shock or autoimmune disease.

Technical terms*1) AT-rich interactive domain 5a (Arid5a)
Arid5a is highly expressed in macrophages in response to lipopolysaccharide (LPS) and controls posttranscriptional
regulation of IL-6 by stabilizing Il6 mRNA by binding to its 3′ UTR*2) Interleukin-6 (IL-6)
This is pro-inflammatory cytokine, is discovered by Kishimoto laboratory of Osaka University*3) Regnase-1
Regnase-1 has been shown to destabilize Il6 mRNA by interacting with a conserved stem-loop motif in the 3′ UTR

Article information
Journal: Proceedings of the National Academy of Science of the USA (Online publishing on Jan. 22, 2018)
Title: “Regulation of inflammatory responses by dynamic subcellular localization of RNA binding protein Arid5a”
Authors: Mitsuru Higaa,b, Masahiro Okab, Yoshitaka Fujihara c , Kazuya Masudaa, Yoshihiro Yonedad and Tadamitsu
Kishimotoa,1.

a)Laboratory of Immune Regulation, Immunology Frontier Research Center, Osaka University, Suita, 565-0871
Osaka, Japanb)

Laboratory of Nuclear Transport Dynamics, National Institutes of Biomedical Innovation, Health and Nutrition,Ibaraki, 567-0085 Osaka, Japanc)Research Institute for Microbial Diseases, Osaka University, Suita, 565-0871 Osaka, Japand)

National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, 567-0085 Osaka, Japan1)

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