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Dimethyl fumarate dampens IL-17-ACT1-TBK1 axis-mediated phosphorylation of Regnase-1 and suppresses IL-17–induced IκB-ζ expression

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Title: Dimethyl fumarate dampens IL-17-ACT1-TBK1 axis-mediated phosphorylation of Regnase-1 and suppresses IL-17–induced IκB-ζ expression
Authors: Ohgakiuchi, Yui Browse this author
Saino, Yuka Browse this author
Muromoto, Ryuta Browse this author →KAKEN DB
Komori, Yuki Browse this author
Sato, Ami Browse this author
Hirashima, Koki Browse this author
Kitai, Yuichi Browse this author →KAKEN DB
Kashiwakura, Jun-ichi Browse this author →KAKEN DB
Oritani, Kenji Browse this author →KAKEN DB
Matsuda, Tadashi Browse this author →KAKEN DB
Keywords: IL-17
mRNA stability
Dimethyl fumarate
Issue Date: 22-Jan-2020
Publisher: Elsevier
Journal Title: Biochemical and Biophysical Research Communications
Volume: 521
Issue: 4
Start Page: 957
End Page: 963
Publisher DOI: 10.1016/j.bbrc.2019.11.036
Abstract: The signaling elicited by the cytokine interleukin-17A (IL-17) is important for antimicrobial defense responses, whereas excessive IL-17 production leads to autoimmune diseases such as psoriasis and multiple sclerosis. IL-17–induced stabilization of mRNAs has been recognized as a unique and important feature of IL-17 signaling. Previously, we demonstrated that IL-17 signaling protein ACT1 is required to counteract constitutive inhibitor of nuclear factor kappa B zeta (IκB-ζ) mRNA degradation by the ribonuclease Regnase-1. However, information about the mechanism of mRNA stabilization in IL-17–stimulated cells remains insufficient. In the present study, we aimed to clarify the mechanism in more detail and identify an agent that can inhibit IL-17–induced mRNA stabilization. Experiments using small interfering RNA and an inhibitor of TANK-binding kinase 1 (TBK1) revealed that TBK1 was required for IκB-ζ mRNA stabilization through Regnase-1 phosphorylation. Intriguingly, this TBK1-mediated phosphorylation of Regnase-1 was suppressed by the addition of dimethyl fumarate (DMF), an electrophilic small molecule that has been used to treat IL-17–related autoimmune diseases. Confocal microscopic observation of the cellular localization of ACT1 revealed that DMF treatment resulted in the disappearance of ACT1 nuclear dots and perinuclear accumulation of ACT1. These results suggested that DMF is a small molecule that compromises IL-17–induced activation of the ACT1-TBK1 pathway, thereby inhibiting IL-17–induced mRNA stabilization.
Rights: © <2020>. This manuscript version is made available under the CC-BY-NC-ND 4.0 license
Type: article (author version)
Appears in Collections:薬学研究院 (Faculty of Pharmaceutical Sciences) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 室本 竜太

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