WDR23 regulates NRF2 independently of KEAP1.

Abstract:

:Cellular adaptation to stress is essential to ensure organismal survival. NRF2/NFE2L2 is a key determinant of xenobiotic stress responses, and loss of negative regulation by the KEAP1-CUL3 proteasome system is implicated in several chemo- and radiation-resistant cancers. Advantageously using C. elegans alongside human cell culture models, we establish a new WDR23-DDB1-CUL4 regulatory axis for NRF2 activity that operates independently of the canonical KEAP1-CUL3 system. WDR23 binds the DIDLID sequence within the Neh2 domain of NRF2 to regulate its stability; this regulation is not dependent on the KEAP1-binding DLG or ETGE motifs. The C-terminal domain of WDR23 is highly conserved and involved in regulation of NRF2 by the DDB1-CUL4 complex. The addition of WDR23 increases cellular sensitivity to cytotoxic chemotherapeutic drugs and suppresses NRF2 in KEAP1-negative cancer cell lines. Together, our 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.

journal_name

PLoS Genet

journal_title

PLoS genetics

authors

Lo JY,Spatola BN,Curran SP

doi

10.1371/journal.pgen.1006762

subject

Has Abstract

pub_date

2017-04-28 00:00:00

pages

e1006762

issue

4

eissn

1553-7390

issn

1553-7404

pii

PGENETICS-D-16-01931

journal_volume

13

pub_type

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