title: Substoichiometric hydroxynonenylation of a single protein recapitulates whole-cell-stimulated antioxidant response.
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.
authors.affiliation: Department of Chemistry and Chemical Biology, Cornell University , Ithaca, New York 14853, United States.
authors.forename: Saba
authors.initials: S
authors.lastname: Parvez
authors.forename: Yuan
authors.initials: Y
authors.lastname: Fu
authors.forename: Jiayang
authors.initials: J
authors.lastname: Li
authors.forename: Marcus J C
authors.initials: MJ
authors.lastname: Long
authors.forename: Hong-Yu
authors.initials: HY
authors.lastname: Lin
authors.forename: Dustin K
authors.initials: DK
authors.lastname: Lee
authors.forename: Gene S
authors.initials: GS
authors.lastname: Hu
authors.forename: Yimon
authors.initials: Y
authors.lastname: Aye
mesh_terms: D000447:Aldehydes / Q000737:chemistry / Q000378:metabolism*; D000975:Antioxidants / Q000737:chemistry / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D018384:Oxidative Stress; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000447:Aldehydes; D000975:Antioxidants; D011506:Proteins; C027576:4-hydroxy-2-nonenal