Substoichiometric
Hydroxynonenylation of a Single
Protein Recapitulates Whole-Cell-Stimulated Antioxidant Response
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Abstract
Lipid-derived
electrophiles (LDEs) that can directly modify proteins
have emerged as important small-molecule cues in cellular decision-making.
However, because these diffusible LDEs can modify many targets [e.g.,
>700 cysteines are modified by the well-known LDE 4-hydroxynonenal
(HNE)], establishing the functional consequences of LDE modification
on individual targets remains devilishly difficult. Whether LDE modifications
on a single protein are biologically sufficient to activate discrete
redox signaling response downstream also remains untested. Herein,
using T-REX (targetable reactive electrophiles and oxidants), an approach
aimed at selectively flipping a single redox switch in cells at a
precise time, we show that a modest level (∼34%) of HNEylation
on a single target is sufficient to elicit the pharmaceutically important
antioxidant response element (ARE) activation, and the resultant strength
of ARE induction recapitulates that observed from whole-cell electrophilic
perturbation. These data provide the first evidence that single-target
LDE modifications are important individual events in mammalian physiology