ur results identify WDR23 as an alternative regulator of NRF2 proteostasis and uncover a cellular pathway that regulates NRF2 activity and capacity for cytoprotection independently of KEAP1.
we identify and confirm the mutations in xrep-2 xrep-3 and xrep-4 The xrep-2 gene is alh-6 an ortholog of a human gene mutated in familial hyperprolinemia. The xrep-3 mutation is a gain-of-function allele of skn-1 The xrep-4 gene is F46F11.6 which encodes a F-box-containing protein. We demonstrate that xrep-4 alters the stability of WDR-23 (xrep-1) a key regulator of SKN-1 (xrep-3).
a missense mutation in the conserved XREP-4 F-box domain that reduces interaction with SKR-1 but not WDR-23 strongly attenuates SKN-1-dependent gene activation. These results are consistent with XREP-4 influencing the SKN-1 stress response by functioning as a bridge between WDR-23 and the ubiquitin ligase component SKR-1.
We also show that SKR-1/2 functions upstream of the WD40 repeat protein WDR-23 which binds to and inhibits SKN-1. Together these results identify a novel p38 MAPK independent signaling mechanism that activates SKN-1 via SKR-1/2 and involves WDR-23.
diverse wdr-23 phenotypes are dependent on SKN-1; beneficial and detrimental phenotypes of wdr-23 and skn-1 can be partially decoupled; SKN-1 activation delays degenerative tissue changes during aging
We'd like to inform you that we have updated our Privacy Notice to comply with Europe’s new General Data Protection Regulation (GDPR) that applies since 25 May 2018.