Substoichiometric hydroxynonenylation of a single protein recapitulates whole-cell-stimulated antioxidant response

Saba Parvez, Yuan Fu, Jiayang Li, Marcus J.C. Long, Hong Yu Lin, Dustin K. Lee, Gene S. Hu, Yimon Aye*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

54 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)10-13
Number of pages4
JournalJournal of the American Chemical Society
Issue number1
StatePublished - Jan 14 2015
Externally publishedYes

ASJC Scopus subject areas

  • Catalysis
  • General Chemistry
  • Biochemistry
  • Colloid and Surface Chemistry


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