WDR-23 and SKN-1/Nrf2 Coordinate with the BLI-3 Dual Oxidase in Response to Iodide-Triggered Oxidative Stress

Abstract

Animals utilize conserved mechanisms to regulate oxidative stress. The C. elegans SKN-1 protein is homologous to the vertebrate Nrf (NF-E2-related factor) family of cap ’n’ collar (CnC) transcription factors and functions as a core regulator of xenobiotic and oxidative stress responses. The WD40 repeat-containing protein WDR-23 is a key negative regulator of SKN-1 activity. We previously found that the oxidative stress induced by excess iodide can be relieved by loss of function in the BLI-3/TSP-15/DOXA-1 dual oxidase complex. To further understand the molecular mechanism of this process, we screened for new mutants that can survive in excess iodide and identified gain-of-function mutations in skn-1 and loss-of-function mutations in wdr-23. The SKN-1C isoform functions in the hypodermis to affect animal’s response to excess iodide, while the SKN-1A isoform appears to play a minor role. wdr-23(lf) can interact with bli-3 mutations in a manner different from skn-1(gf). Transcriptome studies suggest that excess iodide causes developmental arrest largely independent of changes in gene expression, and wdr-23(lf) could affect the expression of a subset of genes by a mechanism different from SKN-1 activation. We propose that WDR-23 and SKN-1 coordinate with the BLI-3/TSP-15/DOXA-1 dual oxidase complex in response to iodide-triggered oxidative stress.

C. elegans heritably adapts to P. vranovensis infection via a mechanism that requires the cysteine synthases cysl-1 and cysl-2

“…4c). Consistent with our findings, multiple previous studies have identified that wdr-23 mutants exhibit increased expression of glutathione-s-transferases, including gst-31 28–30 . We conclude that WDR-23 negatively regulates the expression of gst-31 .…”

“…WDR-23 is a negative regulator of the Nrf2-like transcription factor SKN-1 and the loss of WDR-23 results in SKN-1 activation 31 . Activation of SKN-1 in turn promotes the expression of oxidative stress response genes 30 and mutations in skn-1 suppress many of the defects observed in wdr-23 mutants 31 . We exposed wild-type, skn-1 partial loss-of-function, and wdr-23;skn-1 double mutant adults to BIGb446 and assayed the response of their offspring to BIGb446.…”

Hepatic WDR23 proteostasis mediates insulin clearance by regulating insulin-degrading enzyme

“…In the ubiquitin proteasome system, loss of a substrate receptor leads to a loss in turnover of substrates associated with that receptor [17, 19, 23, 24]. To identify new substrates of WDR23 we performed an unbiased proteomic analysis of liver from WT and Wdr23KO mice.…”

Regulation and Functions of the ER-Associated Nrf1 Transcription Factor

“…Functional and molecular evidence indicates that different protein isoforms of invertebrate SKN-1/CNC are equivalent to different mammalian Nrfs. Both Nrf2 and SKN-1C are regulated in the cytosol by redox-sensitive ubiquitin ligases and regulate oxidative stress responses (Itoh et al 1999;Choe et al 2009;Fukushige et al 2017;Xu et al 2018). Nrf1, SKN-1A, and Drosophila CNC-C all contain an aminoterminal transmembrane domain and mediate stress-responsive regulation of the ubiquitin-proteasome system Radhakrishnan et al 2010;Grimberg et al 2011;Glover-Cutter et al 2013;Lehrbach and Ruvkun 2016).…”