PUBLICATION
Z-REX uncovers a bifurcation in function of Keap1 paralogs
- Authors
- Van Hall-Beauvais, A., Poganik, J.R., Huang, K.T., Parvez, S., Zhao, Y., Lin, H.Y., Liu, X., Long, M.J.C., Aye, Y.
- ID
- ZDB-PUB-221028-35
- Date
- 2022
- Source
- eLIFE 11: (Journal)
- Registered Authors
- Aye, Yimon, Huang, Kuan-Ting, Poganik, Jesse
- Keywords
- biochemistry, chemical biology, zebrafish
- MeSH Terms
-
- Animals
- Antioxidants/metabolism
- Humans
- Kelch-Like ECH-Associated Protein 1/genetics
- Kelch-Like ECH-Associated Protein 1/metabolism
- NF-E2-Related Factor 2*/genetics
- NF-E2-Related Factor 2*/metabolism
- Signal Transduction
- Zebrafish*/metabolism
- PubMed
- 36300632 Full text @ Elife
Citation
Van Hall-Beauvais, A., Poganik, J.R., Huang, K.T., Parvez, S., Zhao, Y., Lin, H.Y., Liu, X., Long, M.J.C., Aye, Y. (2022) Z-REX uncovers a bifurcation in function of Keap1 paralogs. eLIFE. 11:.
Abstract
Studying electrophile signaling is marred by difficulties in parsing changes in pathway flux attributable to on-target, vis-à-vis off-target, modifications. By combining bolus dosing, knockdown, and Z-REX-a tool investigating on-target/on-pathway electrophile signaling, we document that electrophile labeling of one zebrafish-Keap1-paralog (zKeap1b) stimulates Nrf2- driven antioxidant response (AR) signaling (like the human-ortholog). Conversely, zKeap1a is a dominant-negative regulator of electrophile-promoted Nrf2-signaling, and itself is nonpermissive for electrophile-induced Nrf2-upregulation. This behavior is recapitulated in human cells, wherein following electrophile treatment: (1) zKeap1b-transfected cells are permissive for augmented AR-signaling through reduced zKeap1b-Nrf2 binding; (2) zKeap1a-transfected cells are non-permissive for AR-upregulation, as zKeap1a-Nrf2 binding capacity remains unaltered; (3) 1:1 ZKeap1a:zKeap1b-transfected cells show no Nrf2-release from the Keap1-complex, rendering these cells unable to upregulate AR. We identified a zKeap1a-specific point-mutation (C273I) responsible for zKeap1a's behavior. Human-Keap1(C273I), of known diminished Nrf2-regulatory capacity, dominantly muted electrophile-induced Nrf2-signaling. These studies highlight divergent and interdependent electrophile signaling behaviors, despite conserved electrophile sensing.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping