KARS mediates intra-translational deposition of N6-acetyl-L-lysine in nascent proteins to contribute the acetylome in cells

N 6-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-derived N 6-acetyl- L -lysine in nascent proteins to contribute the acetylome in cells. Acetylated dietary protein is a direct source of N 6-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 with N 6- acetyl- L -lysyl-AMP and pyrophosphate, together with in vitro biochemical assays, we learned that KARS can utilize N 6-acetyl- L -lysine to produce N 6-acetyl- L -lysyl-AMP and transfers the N 6-acetyl- L -lysyl-moiety to lysine cognate tRNA to generate N 6-acetyl- L - lysyl-tRNA, which introduces N 6-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. ### Competing Interest Statement The authors have declared no competing interest.