FIG. 7.

Different modes of redox modulation and their effects on Nrf2 activation. (A) Both Keap1 and TrxR1 are subject to inhibition by electrophiles and ROS, which, in turn, leads to activation of Nrf2. The interplay between Keap1, TrxR1, and Nrf2 is constituted of a complex web of interactions. Here, it is proposed that TrxR1 targeting is part of the mechanisms regulating Nrf2 activation, as summarized in the figure and discussed further in the text. (B) Active TrxR1 is proposed to act as a gatekeeper to prevent Nrf2 activation. Direct inactivation of the enzyme promotes Nrf2 activation, as seen in Txnrd1 knockout or knockdown models, or under selenium deprivation conditions. In addition, the formation of SecTRAPs can promote a very strong Nrf2 activation, by means of ROS production from converted TrxR1 protein having NADPH oxidase activity, in addition to a loss of reductive capacity. These mechanisms together identify TrxR1 as a potent regulator of Nrf2 activation. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars