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

Ohgakiuchi, Yui; Saino, Yuka; Muromoto, Ryuta; Komori, Yuki; Sato, Ami; Hirashima, Koki; Kitai, Yuichi; Kashiwakura, Jun-ichi; Oritani, Kenji; Matsuda, Tadashi

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

Ohgakiuchi, Yui; Saino, Yuka; Muromoto, Ryuta et al.

Biochemical and Biophysical Research Communications, 2020, 521(4), 957-963

Permalink : https://hdl.handle.net/2115/82065

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アクセス権	open access
URI	https://hdl.handle.net/2115/82065
タイトル	Dimethyl fumarate dampens IL-17-ACT1-TBK1 axis-mediated phosphorylation of Regnase-1 and suppresses IL-17–induced IκB-ζ expression
著者	Ohgakiuchi, Yui ; Saino, Yuka ; Muromoto, Ryuta ; Komori, Yuki ; Sato, Ami ; Hirashima, Koki ; Kitai, Yuichi ; Kashiwakura, Jun-ichi ; Oritani, Kenji ; Matsuda, Tadashi
著者名 Ohgakiuchi, Yui
著者名 Saino, Yuka
e-Rad_Researcher 30455597 著者名 Muromoto, Ryuta
著者名 Komori, Yuki
著者名 Sato, Ami
著者名 Hirashima, Koki
e-Rad_Researcher 90756165 著者名 Kitai, Yuichi
e-Rad_Researcher 90373290 著者名 Kashiwakura, Jun-ichi
e-Rad_Researcher 70324762 著者名 Oritani, Kenji
e-Rad_Researcher 20212219 著者名 Matsuda, Tadashi
言語	英語
キーワード	IL-17
	mRNA stability
	Dimethyl fumarate
	IκB-ζ
	Regnase-1
発行日	2020-01-22
出版者	Elsevier
収録物名	Biochemical and Biophysical Research Communications
巻(号)	521(4)
ページ	957-963
抄録	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.
資源タイプ	学術雑誌論文
出版タイプ	Accepted Manuscript
権利情報	Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
権利情報	© <2020>. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/
PISSN	0006-291X
関連情報 (isVersionOf)	出版社版DOI https://doi.org/10.1016/j.bbrc.2019.11.036