PUBLICATION
Wdr1 and cofilin are necessary mediators of immune-cell-specific apoptosis triggered by Tecfidera
- Authors
- Poganik, J.R., Huang, K.T., Parvez, S., Zhao, Y., Raja, S., Long, M.J.C., Aye, Y.
- ID
- ZDB-PUB-211022-48
- Date
- 2021
- Source
- Nature communications 12: 5736 (Journal)
- Registered Authors
- Aye, Yimon, Huang, Kuan-Ting, Poganik, Jesse
- Keywords
- none
- Datasets
- GEO:GSE135190
- MeSH Terms
-
- Actin Depolymerizing Factors/metabolism*
- Animals
- Animals, Genetically Modified
- Apoptosis/drug effects
- Apoptosis/immunology
- Dimethyl Fumarate/pharmacology*
- Embryo, Mammalian
- Embryo, Nonmammalian
- Gene Knockdown Techniques
- HEK293 Cells
- Humans
- Immunity, Innate/drug effects
- Immunosuppressive Agents/pharmacology*
- Kelch-Like ECH-Associated Protein 1/genetics
- Kelch-Like ECH-Associated Protein 1/metabolism*
- Macrophages/drug effects
- Macrophages/immunology
- Macrophages/metabolism
- Mice
- Microfilament Proteins/metabolism*
- Neutrophils/drug effects
- Neutrophils/immunology
- Neutrophils/metabolism
- Signal Transduction/drug effects
- Signal Transduction/immunology
- Zebrafish
- PubMed
- 34593792 Full text @ Nat. Commun.
Citation
Poganik, J.R., Huang, K.T., Parvez, S., Zhao, Y., Raja, S., Long, M.J.C., Aye, Y. (2021) Wdr1 and cofilin are necessary mediators of immune-cell-specific apoptosis triggered by Tecfidera. Nature communications. 12:5736.
Abstract
Despite the emerging importance of reactive electrophilic drugs, deconvolution of their principal targets remains difficult. The lack of genetic tractability/interventions and reliance on secondary validation using other non-specific compounds frequently complicate the earmarking of individual binders as functionally- or phenotypically-sufficient pathway regulators. Using a redox-targeting approach to interrogate how on-target binding of pleiotropic electrophiles translates to a phenotypic output in vivo, we here systematically track the molecular components attributable to innate immune cell toxicity of the electrophilic-drug dimethyl fumarate (Tecfidera®). In a process largely independent of canonical Keap1/Nrf2-signaling, Keap1-specific modification triggers mitochondrial-targeted neutrophil/macrophage apoptosis. On-target Keap1-ligand-engagement is accompanied by dissociation of Wdr1 from Keap1 and subsequent coordination with cofilin, intercepting Bax. This phagocytic-specific cell-killing program is recapitulated by whole-animal administration of dimethyl fumarate, where individual depletions of the players identified above robustly suppress apoptosis.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping