Wdr1 and cofilin are necessary mediators of immune-cell-specific apoptosis triggered by Tecfidera

Journal article

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

Authors: Poganik, JR; Huang, K-T; Parvez, S; Zhao, Y; Raja, S

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Nature Research
• Journal: Nature Communications
• Volume: 12
• Issue: 1
• Pages: 5736-5736
• Publication date: 2021-09-30
• DOI: 10.1038/s41467-021-25466-x
• EISSN: 2041-1723
• ISSN: 2041-1723
• Language: English
• Keywords: Chemistry; KEAP1; Biology; Innate immune system; Apoptosis; Gene; Transcription factor; Immunology; Biochemistry; Cell biology; Computational biology; Immune system