WDR23 regulates NRF2 independently of KEAP1.
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. eleg...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2017-04-01
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| Series: | PLoS Genetics |
| Online Access: | http://europepmc.org/articles/PMC5428976?pdf=render |
| _version_ | 1828303339392073728 |
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| author | Jacqueline Y Lo Brett N Spatola Sean P Curran |
| author_facet | Jacqueline Y Lo Brett N Spatola Sean P Curran |
| author_sort | Jacqueline Y Lo |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-13T13:51:09Z |
| format | Article |
| id | doaj.art-79081bcae5a24972ac7c4dbb5706f365 |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-04-13T13:51:09Z |
| publishDate | 2017-04-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj.art-79081bcae5a24972ac7c4dbb5706f3652022-12-22T02:44:19ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042017-04-01134e100676210.1371/journal.pgen.1006762WDR23 regulates NRF2 independently of KEAP1.Jacqueline Y LoBrett N SpatolaSean P CurranCellular 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.http://europepmc.org/articles/PMC5428976?pdf=render |
| spellingShingle | Jacqueline Y Lo Brett N Spatola Sean P Curran WDR23 regulates NRF2 independently of KEAP1. PLoS Genetics |
| title | WDR23 regulates NRF2 independently of KEAP1. |
| title_full | WDR23 regulates NRF2 independently of KEAP1. |
| title_fullStr | WDR23 regulates NRF2 independently of KEAP1. |
| title_full_unstemmed | WDR23 regulates NRF2 independently of KEAP1. |
| title_short | WDR23 regulates NRF2 independently of KEAP1. |
| title_sort | wdr23 regulates nrf2 independently of keap1 |
| url | http://europepmc.org/articles/PMC5428976?pdf=render |
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