Redox cycling of 1,2-naphthoquinone by thioredoxin1 through Cys32 and Cys35 causes inhibition of its catalytic activity and activation of ASK1/p38 signaling

Chemical Research in Toxicology
Yasuhiro ShinkaiYoshito Kumagai

Abstract

1,2-Naphthoquinone (1,2-NQ) is an atmospheric chemical capable of (1) redox cycling with electron donors and (2) covalent modification of nucleophilic groups on proteins. In the present study, we investigated its interaction with the redox protein, thioredoxin1 (Trx1), which led to oxidative stress-dependent cell damage. In experiments with purified wild-type Trx1 and its double mutant (32S/35S Trx1), we found that incubation of Trx1 with 1,2-NQ resulted in a redox cycling reaction, generating superoxide and hydrogen peroxide involving Cys32 and Cys35 and an arylation reaction resulting in covalent modification of Lys85 together with a loss of Trx activity. A significant fraction of the lost Trx1 activity following interaction with 1,2-NQ was restored by dithiothreitol. Exposure of RAW264.7 cells to 1,2-NQ generated reactive oxygen species (ROS) and caused a decrease in Trx activity. Trx is a negative regulator of apoptosis signal-regulating kinase 1 (ASK1), and under the conditions of the experiment, 1,2-NQ activated ASK1 and p38, leading to PARP cleavage and apoptotic cell death that were blocked by pretreatment with polyethylene glycol-catalase. These results suggest that Trx1 readily undergoes oxidative modification by 1,2-...Continue Reading

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Citations

Nov 26, 2015·Chemical Research in Toxicology·Phillip A WagesJames Samet
May 31, 2013·The Journal of Toxicological Sciences·Takashi ToyamaYoshito Kumagai
Jan 15, 2020·The Journal of Toxicological Sciences·Yasuhiro ShinkaiYoshito Kumagai
Sep 4, 2020·Cardiovascular Toxicology·Kumuda C DasJaganathan Subramani
Dec 19, 2016·Chemical Research in Toxicology·Carlos Morales BetanzosDaniel C Liebler

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