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Reactive electrophilic species (RES) have emerged in recent years as bona fide cellular signaling mediators, controlling myriad cellular processes. RES such as the lipid-derived electrophile (LDE) 4-hydroxynonenal (HNE) engage specific targets in cells featuring kinetically-privileged cysteine residues able to react rapidly with the RES. These modification events trigger signaling cascades to produce a cellular response. The growth of the RES signaling field has coincided with an explosion of interest in covalent drugs, which can target kinetically-privileged cysteines to produce a therapeutic effect. For instance, dimethyl fumarate (DMF; Tecfidera®)—a relatively simple electrophile—was approved in 2013 for the treatment of multiple sclerosis, and is now a multi-billion dollar drug. In spite of these advances, electrophile signaling and mechanisms of action of drugs that are believed to function through electrophile-signaling-like mechanisms remain particularly challenging to study. The pleiotropic nature of these molecules along with the often pleiotropic effects engendered by cellular electrophile exposure make pinning down the mechanisms by which they evoke cellular responses difficult. This is underscored by the fact that DMF was approved without a clear mechanism of action, and prior to our work there existed no identified target of DMF whose modification was fully sufficient to explain the clinical effects of this drug, namely induction of apoptosis in immune cells. Herein, we leveraged our lab’s Targetable Reactive Electrophiles and Oxidants (T-REX) electrophile delivery platform to delineate a novel signaling cascade controlling apoptosis of neutrophils and macrophages in zebrafish exposed to DMF. Unlike previous studies proposing targets of DMF, knockdown or inhibition of the protein players we identified to control the effects of DMF—Keap1, Wdr1, Cfl1, and Bax—was able to fully suppress apoptosis of immune cells, clearly demonstrating the necessity of these proteins in DMF’s mechanism of action. Moving to the realm of RES signaling in regulation of mRNA, we sought to characterize the reported electrophile sensing abilities of two key, disease-relevant mRNA binding proteins (mRBPs), HuR and AUF1. These studies led us to identify an unexpected novel regulatory axis controlling the Nrf2-driven antioxidant response (AR), a key stress response pathway upregulated in cells exposed to oxidants and RES. Testifying to the pleiotropic nature of these regulatory events, HuR regulation of Nrf2-mRNA produced divergent effects on AR under non-stimulated and HNE-stimulated conditions. Furthermore, in contrast to previous reports suggesting the electrophile-sensing abilities of both HuR and AUF1, we found that only HuR features kinetically privileged HNE-sensing ability. Taken together, these studies have revealed novel signaling events controlling diverse cellular pathways/processes engendered by RES. Additionally, identification of a sufficient mechanism by which DMF functions and the privileged RES sensing ability of HuR point to inroads for novel/improved therapeutics for these druggable pathways.

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299 pages

Supplemental file(s) description: Table A2.3, Table A1.4, Table A1.2.


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Aye, Yimon

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Crane, Brian
Fetcho, Joseph

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Chemistry and Chemical Biology

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Ph. D., Chemistry and Chemical Biology

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Doctor of Philosophy

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dissertation or thesis

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