MassIVE MSV000082101

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Electrophilic stress induced by itaconate and its derivatives regulates ATF3-IKBZ inflammatory axis independently of Nrf2 induction

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Description

Metabolic regulation recently emerged as a novel powerful principle guiding immune responses. The natural metabolite itaconate and its membrane permeable derivative dimethyl itaconate (DI) were recently shown to selectively inhibit a subset of cytokines during macrophage activation, yet the precise mechanism of this effect remained unclear. We show here that itaconate/DI react with glutathione and subsequently induce both Nrf2-dependent and Nrf2-independent stress responses. We find that the striking selectivity of DI action stems from the inhibitory effects of electrophilic stress on IKBZ protein translation, leading to the inhibition of only the secondary wave of NF-KB signaling. We find that IKBZ regulation occurs in an Nrf2-independent manner, and identify ATF3 as a key mediator of the immunosuppression. [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: primary mouse dendritic cells, TMT-labeling, dimethyl itaconate (DI), lipopolysaccharide (LPS)

Contact

Principal Investigators:
(in alphabetical order) 		Marko Jovanovic, Columbia University, USA
Submitting User: maki_vienna

Publications

Bambouskova M, Gorvel L, Lampropoulou V, Sergushichev A, Loginicheva E, Johnson K, Korenfeld D, Mathyer ME, Kim H, Huang LH, Duncan D, Bregman H, Keskin A, Santeford A, Apte RS, Sehgal R, Johnson B, Amarasinghe GK, Soares MP, Satoh T, Akira S, Hai T, de Guzman Strong C, Auclair K, Roddy TP, Biller SA, Jovanovic M, Klechevsky E, Stewart KM, Randolph GJ, Artyomov MN.
Electrophilic properties of itaconate and derivatives regulate the I?B?-ATF3 inflammatory axis.
Nature. 2018 Apr;556(7702):501-504. Epub 2018 Apr 18.

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