KARS mediates intra-translational deposition ofN⁶-acetyl-L-lysine in nascent proteins to contribute the acetylome in cells

AbstractN6-acetyl-L-lysine residue is abundant in dietary protein but less is known about its potential influences on the diet-consumers. We herein report that KARS mediates intra- translational deposition of diet-derivedN6-acetyl-L-lysine in nascent proteins to contribute the acetylome in cells. Acetylated dietary protein is a direct source ofN6-acetyl-L-lysine that can widely and substantially contribute the acetylome in multiple organs of mice. By analyzing the co-crystal structure of Lysyl-tRNA synthetase (KARS) in complex withN6- acetyl-L-lysyl-AMP and pyrophosphate, together within vitrobiochemical assays, we learned that KARS can utilizeN6-acetyl-L-lysine to produceN6-acetyl-L-lysyl-AMP and transfers theN6-acetyl-L-lysyl-moiety to lysine cognate tRNA to generateN6-acetyl-L- lysyl-tRNA, which introducesN6-acetyl-L-lysine into growing nascent polypeptide and intra-translationally results in protein acetylation. This undocumented protein modification mechanism is inherently different from post-translational modification (PTM) and termed as intra-translational modification (ITM). ITM can functionally mimic PTM mechanisms to deposit acetylation in histones to decondense chromatin. It can also modify PTM- inaccessible regions that are buried inside and functionally important to proteins. ITM is expected to extend the repertoire of acetylome and improve our understandings in protein modification modes in cells.