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Detection and comparison of three lactylation isomers, KL-la, KD-la and Kce

ABSTRACT: We recently identified lysine L-lactylation (KL-la) on histones that can be labelled by L-lactate, the end-product of glycolysis. KL-la has two structural isomers, namely N--(carboxyethyl) lysine (Kce) and lysine D-lactylation (KD-la), which can also be caused by metabolites associated with glycolysis. It is unknown if perturbations of glycolysis can lead to dysregulation of KD-la and Kce, in addition to KL-la. Further, current methods have a difficulty to distinguish among these isomers in cellular contexts. To investigate these questions, we first generated specific antibodies against each one of these three modifications. These reagents enable us to distinguish these three isomers. We demonstrated that KL-la, but not KD-la and Kce, is dynamically regulated by glycolysis. KD-la and Kce occur mainly when the major glycolytic pathway is blocked downstream or when the glyoxalase system is incomplete. This result was also independently confirmed by orthogonal HPLC-mass spectrometry, showing that KL-la is the predominant isomer of lactylation on cellular histones. Finally, we demonstrated that lactyl-CoA, an intermediate between L-lactate and lactylation, is dynamically regulated by glycolysis and is positively correlated with KL-la. Thus, our study clearly shows that KL-la, but not KD-la and Kce, is the major glycolytic- and the Warburg-effect associated responsive modification in cells.

ORGANISM(S): Homo Sapiens

SUBMITTER: Yingming Zhao

PROVIDER: PXD040840 | iProX | Mon Mar 13 00:00:00 GMT 2023

REPOSITORIES: iProX

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