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Dimethyl fumarate regulates the IL‐17‐ACT1‐TBK1 axis‐mediated IκB‐ζ expression by influencing the phosphorylation of Regnase‐1
Author(s) -
Matsuda Tadashi,
Ohagakiuchi Yui,
Saino Yuka,
Komori Yuki,
Sato Ami,
Hirashima Koki,
KItai Yuichi,
Kashiwakura Jun-ichi,
Oritani Kenji,
Muromoto Ryuta
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.03845
Subject(s) - phosphorylation , chemistry , signal transduction , microbiology and biotechnology , biology , biochemistry
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. We previously demonstrated that an 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. In the present study, we tried to clarify this mechanism in more detail and identify an agent that can inhibit IL‐17–induced mRNA stabilization. Experiments using siRNA and an inhibitor of TANK‐binding kinase 1 (TBK1) revealed that TBK1 was also required for IκB‐ζ mRNA stabilization through Regnase‐1 phosphorylation. Interestingly, this TBK1‐mediated phosphorylation of Regnase‐1 was suppressed by the addition of an electrophilic small molecule, dimethyl fumarate (DMF) that has been used to treat IL‐17–related autoimmune diseases. Furthermore, 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. Support or Funding Information This work was supported in part by the Japan Society for the Promotion of Science (JSPS) KAKENHI grant (numbers 254600560, 17K08263, and 19H03364).