Genetic code expansion reveals site-specific lactylation in living cells reshapes protein functions

Chang Shao, Shuo Tang, Siqin Yu, Chenguang Liu, Yueyang Zhang, Tianyan Wan, Zimeng He, Qi Yuan, Shihan Wu, Hanqing Zhang, Ning Wan, Mengru Zhan, Ren Xiang Tan, Haiping Hao, Hui Ye () and Nanxi Wang ()
Additional contact information
Chang Shao: Tongjiaxiang No. 24
Shuo Tang: Xianlindadao No. 138
Siqin Yu: Tongjiaxiang No. 24
Chenguang Liu: Tongjiaxiang No. 24
Yueyang Zhang: Tongjiaxiang No. 24
Tianyan Wan: Xianlindadao No. 138
Zimeng He: Tongjiaxiang No. 24
Qi Yuan: Tongjiaxiang No. 24
Shihan Wu: Xianlindadao No. 138
Hanqing Zhang: Tongjiaxiang No. 24
Ning Wan: Tongjiaxiang No. 24
Mengru Zhan: Xianlindadao No. 138
Ren Xiang Tan: Xianlindadao No. 138
Haiping Hao: Tongjiaxiang No. 24
Hui Ye: Tongjiaxiang No. 24
Nanxi Wang: Xianlindadao No. 138

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract Protein lactylation is an emerging field. To advance the exploration of its biological functions, here we develop a comprehensive workflow that integrates proteomics to identify lactylated sites, genetic code expansion (GCE) for the expression of site-specifically lactylated proteins in living cells, and an integrated functional analysis (IFA) platform to evaluate their biological effects. Using a combined wet-and-dry-lab proteomics strategy, we identify a conserved lactylation at ALDOA-K147, which we hypothesize plays a significant biological role. Expression of this site-specifically lactylated ALDOA in mammalian cells reveals that this modification not only inhibits enzymatic activity but also induces gain-of-function effects. These effects reshaped ALDOA functionality by enhancing protein stability, promoting nuclear translocation, regulating adhesion-related gene expression, altering cell morphology and modulating ALDOA-interacting proteins. Our findings highlight the utility of the GCE-based workflow in establishing causal relationships between specific lactylation events and both target-specific and cell-wide changes, advancing our understanding of protein lactylation’s functional impact.

Date: 2025
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DOI: 10.1038/s41467-024-55165-2

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