Yi Zhao

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Z-REX uncovers a bifurcation in function of Keap1 paralogs

Yimon Aye, Kuan-Ting Huang, Xuyu Liu, Jesse Poganik, Yi Zhao

Studying electrophile signaling is marred by difficulties in parsing changes in pathway flux attributable to on-target, vis-& agrave;-vis off-target, modifications. By combining bolus dosing, knockdown, and Z- REX & mdash;a tool investigating on- target/on-pathway electrophile signaling, we document that electrophile labeling of one zebrafish- Keap1- paralog (zKeap1b) stimulates Nrf2driven antioxidant response (AR) signaling (like the human-ortholog). Conversely, zKeap1a is a dominant-negative regulator of electrophile-promoted Nrf2signaling, and itself is nonpermissive for electrophile-induced Nrf2upregulation. This behavior is recapitulated in human cells: (1) zKeap1b-expressing cells are permissive for augmented AR-signaling through reduced zKeap1b-Nrf2 binding following whole -cell electrophile treatment; (2) zKeap1a-expressing cells are non-permissive for AR-upregulation, as zKeap1a-Nrf2 binding capacity remains unaltered upon whole -cell electrophile exposure; (3) 1:1 ZKeap1a:zKeap1b-co-expressing cells show no Nrf2release from the Keap1-complex following whole -cell electrophile administration, rendering these cells unable to upregulate AR. We identified a zKeap1a-specific point-mutation (C273I) responsible for zKeap1a's behavior during electrophilic stress. Human-Keap1(C273I), of known diminished Nrf2regulatory capacity, dominantly muted electrophile-induced Nrf2signaling. These studies highlight divergent and interdependent electrophile signaling behaviors, despite conserved electrophile sensing.

eLIFE SCIENCES PUBL LTD2022

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The mechanism-of-action of many electrohilic drugs remains poorly understood. Here, the authors use a redox-targeting approach to elucidate the basis for the innate immune cell toxicity of dimethyl fumarate, showing that it modifies Keap1 to trigger mitochondrial-targeted neutrophil/macrophage apoptosis. 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 (R)). 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.

NATURE PORTFOLIO2021

Clofarabine Commandeers the RNR-alpha-ZRANB3 Nuclear Signaling Axis

Yimon Aye, Yi Zhao

Ribonucleotide reductase (RNR) is an essential enzyme in DNA biogenesis and a target of several chemotherapeutics. Here, we investigate how antileukemic drugs (e.g., clofarabine [CIF]) that target one of the two subunits of RNR, RNR-alpha, affect noncanonical RNR-alpha functions. We discovered that these clinically approved RNR-inhibiting dATP-analogs inhibit growth by also targeting ZRANB3-a recently identified DNA synthesis promoter and nuclear-localized interactor of RNR-alpha. Remarkably, in early time points following drug treatment, ZRANB3 targeting accounted for most of the drug-induced DNA synthesis suppression and multiple cell types featuring ZRANB3 knockout/knockdown were resistant to these drugs. In addition, ZRANB3 plays a major role in regulating tumor invasion and H-ras(G12V)-promoted transformation in a manner dependent on the recently discovered interactome of RNR-alpha involving select cytosolic-/nuclear-localized protein players. The H-ras(G12V)-promoted transformation-which we show requires ZRANB3-supported DNA synthesis-was efficiently suppressed by ClF. Such overlookedmechanisms of action of approved drugs and a previously unappreciated example of non-oncogene addiction, which is suppressed by RNR-alpha, may advance cancer interventions.

CELL PRESS2020