Electrophilic stress induced by itaconate and its derivatives regulates ATF3-IKBZ inflammatory axis independently of Nrf2 induction
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ABSTRACT: 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.
INSTRUMENT(S): Q Exactive
ORGANISM(S): Mus Musculus (ncbitaxon:10090)
SUBMITTER: 
Marko Jovanovic
PROVIDER: MSV000082101 | MassIVE | Sun Feb 25 22:23:00 GMT 2018
REPOSITORIES: MassIVE
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