Trivalent chromium interacts directly with acetylated lysine

Hexavalent chromium Cr(VI), a well-established human carcinogen, induces systemic toxicity affecting reproductive, neurological, hepatic, and immune systems. The broad spectrum of its toxicity implies mechanisms of action that transcend organ-specific or cell type-restricted pathways. Protein interactions have been proposed as a mechanism underlying Cr(VI) toxicity and carcinogenicity. To address gaps in understanding the molecular effect of Cr(VI), particularly the distinct roles of its two stable oxidation states—Cr(VI) and the trivalent form Cr(III) —we employed high-resolution mass spectrometry to identify the protein targets, compare valence-state-specific interactions (Cr(VI) vs. Cr(III)), and map the specific amino acid residues involved. In synthesized histone peptides, we demonstrated that it is Cr(III), rather than Cr(VI), that directly binds to acetylated lysine residues. Further, in cellular models exposed to Cr(VI), we identified 15 Cr-binding proteins, all of which were acetylated, with site-specific information of interacting amino acids. Collectively, these findings provide new evidence that Cr(III), generated via intracellular reduction of Cr(VI), directly binds to post-translationally modified proteins on acetylated lysine residues. This work advances a molecular mechanism wherein Cr(VI) exerts toxicity via its reduced trivalent form, Cr(III), highlighting the critical putative role of protein acetylation in mediating Cr-induced damage.