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

Jesse R. Poganik, Kuan-Ting Huang, Saba Parvez, Yi Zhao, Sruthi Raja, Marcus J. C. Long () and Yimon Aye ()
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Jesse R. Poganik: Swiss Federal Institute of Technology Lausanne (EPFL)
Kuan-Ting Huang: Swiss Federal Institute of Technology Lausanne (EPFL)
Saba Parvez: University of Utah
Yi Zhao: BayRay Innovation Center, Shenzhen Bay Laboratory (SZBL)
Sruthi Raja: Swiss Federal Institute of Technology Lausanne (EPFL)
Marcus J. C. Long: University of Lausanne (UNIL)
Yimon Aye: Swiss Federal Institute of Technology Lausanne (EPFL)

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-25466-x

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