Abstract
<jats:p> During pathogen infection, the <jats:italic>C. elegans</jats:italic> transcription factor SKN-1 is activated through the p38 MAPK cascade to protect against oxidative damage and promote host survival. SKN-1, the functional ortholog of the mammalian Nrf family of transcription factors, participates in various biological processes and is subject to complex regulation. In this study, we identify a previously unrecognized role for LIN-23 in regulating SKN-1 during adult stress conditions. LIN-23 is an F-box protein that functions as the substrate recognition component of the SkpCullinF-box (SCF) E3 ubiquitin ligase complex and has been implicated in diverse cellular processes, including cell cycle regulation, neurite outgrowth, and centrosome duplication. Although LIN-23 has previously been reported to negatively regulate SKN-1 in other contexts, our findings demonstrate that during pathogen exposure, LIN-23 acts as a positive regulator of SKN-1 activity. Specifically, loss of LIN-23 reduced SKN-1 activity and decreased survival of infected adult animals. Having established this novel relationship between LIN-23 and SKN-1, we investigated the mechanism by which LIN-23 regulates SKN-1 activity. Because SKN-1 activation occurs via the p38 MAPK signaling pathway, followed by nuclear localization, we examined whether LIN-23 influences these events, but observed no decrease in p38 MAPK phosphorylation or SKN-1 nuclear localization. Instead, we provide evidence that LIN-23 function is dependent on WDR-23, a well-established negative regulator of SKN-1. A model is proposed in which LIN-23 promotes SKN-1 activity by targeting nuclear WDR-23 for degradation. </jats:p>