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.
Highlights
In response to environmental and cellular stress, organisms must activate specific pathways to defend and protect against damage[1,2,3]
KEAP1 has been the most highly studied regulator of NRF2, as mutations in KEAP1, which result in uncontrolled activation of NRF2 and chemo-resistance, are found in many aggressive cancers
WDR-23 is the major regulator of SKN-1 activity, which is the C. elegans equivalent to mammalian NRF2/NFE2L2
Summary
In response to environmental and cellular stress, organisms must activate specific pathways to defend and protect against damage[1,2,3]. Such stressors include electrophiles, pathogens, and xenobiotics, many of which are carcinogens and activate the conserved cap-n-collar transcription factor NRF2 (nuclear factor E2-related factor) stress response pathway[2, 4]. The regulation of NRF2 is of particular importance to the progression of human diseases where oxidative stress plays a mechanistic role, including: cancer[12], inflammation[13], neurodegeneration[14], cardiovascular diseases[15], and even wound repair and regeneration[16]. Recent studies allude to additional, but unidentified, layers of regulation that are independent of KEAP1[20]
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