title: Histone Ketoamide Adduction by 4-Oxo-2-nonenal Is a Reversible Posttranslational Modification Regulated by Sirt2.
abstract: Lipid-derived electrophiles (LDEs) directly modify proteins to modulate cellular signaling pathways in response to oxidative stress. One such LDE, 4-oxo-2-nonenal (4-ONE), has recently been found to target histones and interfere with histone assembly into nucleosomes. Unlike other LDEs that preferentially modify cysteine via nucleophilic Michael addition, 4-ONE reacts with histone lysine residues to form a new histone modification, gamma-oxononanoylation (Kgon). However, it remains unclear whether Kgon can cause irreversible damage or be regulated by enzymes "erasing" this nonenzymatic modification. Here, we report that human Sirt2 catalyzes the removal of histone Kgon. Among the tested human sirtuins, Sirt2 showed robust deacylase activity toward the Kgon-carrying histone peptides in vitro. We use alkynyl-4-ONE as a chemical reporter for Kgon to demonstrate that Sirt2 is responsible for removing histone Kgon in cells. Furthermore, we develop a ketone-reactive chemical probe to detect histones modified by endogenous 4-ONE in macrophages in response to inflammatory stimulation. Using this probe, we show Sirt2 as a deacylase able to control histone Kgon in stimulated macrophages. This study unravels a new mechanism for the regulation of LDE-derived protein posttranslational modifications, as well as a novel role played by Sirt2 as a histone Kgon deacylase in cytoprotective signaling responses.
authors.affiliation: Department of Chemistry and ‡School of Biomedical Sciences, The University of Hong Kong , Pokfulam Road, Hong Kong, China.
authors.forename: Yiwen
authors.initials: Y
authors.lastname: Cui
authors.affiliation: Department of Chemistry and ‡School of Biomedical Sciences, The University of Hong Kong , Pokfulam Road, Hong Kong, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Chemistry and ‡School of Biomedical Sciences, The University of Hong Kong , Pokfulam Road, Hong Kong, China.
authors.forename: Jianwei
authors.initials: J
authors.lastname: Lin
authors.affiliation: Department of Chemistry and ‡School of Biomedical Sciences, The University of Hong Kong , Pokfulam Road, Hong Kong, China.
authors.forename: Quan
authors.initials: Q
authors.lastname: Hao
authors.affiliation: Department of Chemistry and ‡School of Biomedical Sciences, The University of Hong Kong , Pokfulam Road, Hong Kong, China.
authors.forename: Xiang David
authors.identifier: 0000-0002-2797-4134
authors.initials: XD
authors.lastname: Li
mesh_terms: D000447:Aldehydes / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D006367:HeLa Cells; D042421:Histone Code; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D011499:Protein Processing, Post-Translational; D000067996:RAW 264.7 Cells; D056565:Sirtuin 2 / Q000378:metabolism*
chemical_list: C403894:4-oxo-2-nonenal; D000447:Aldehydes; D006657:Histones; C474199:SIRT2 protein, human; D056565:Sirtuin 2; D008239:Lysine