Issue 20, 2022

A bioorthogonal chemical reporter for the detection and identification of protein lactylation

Abstract

L-Lactylation is a recently discovered post-translational modification occurring on histone lysine residues to regulate gene expression. However, the substrate scope of lactylation, especially that in non-histone proteins, remains unknown, largely due to the limitations of current methods for analyzing lactylated proteins. Herein, we report an alkynyl-functionalized bioorthogonal chemical reporter, YnLac, for the detection and identification of protein lactylation in mammalian cells. Our in-gel fluorescence and chemical proteomic analyses show that YnLac is metabolically incorporated into lactylated proteins and directly labels known lactylated lysines of histones. We further apply YnLac to the proteome-wide profiling of lactylation, revealing many novel modification sites in non-histone proteins for the first time. Moreover, we demonstrate that lactylation of a newly identified substrate protein PARP1 regulates its ADP-ribosylation activity. Our study thus provides a powerful chemical tool for characterizing protein lactylation and greatly expands our understanding of substrate proteins and functions of this new modification.

Graphical abstract: A bioorthogonal chemical reporter for the detection and identification of protein lactylation

Supplementary files

Article information

Article type
Edge Article
Submitted
11 Febr. 2022
Accepted
26 Apr. 2022
First published
26 Apr. 2022
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2022,13, 6019-6027

A bioorthogonal chemical reporter for the detection and identification of protein lactylation

Y. Sun, Y. Chen and T. Peng, Chem. Sci., 2022, 13, 6019 DOI: 10.1039/D2SC00918H

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