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Uncovering ubiquitous protein lactylation

Nature Methods volume 19, pages 793–794 (2022)Cite this article

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A diagnostic fragment ion in tandem mass spectrometry enables confident protein lactylation assignment and the discovery of broad lysine modification beyond histones.

As the end product of glycolysis, lactate has long been considered a waste product that can cause muscle fatigue and potential tissue damage. Research since the 1970s has shifted the lactate paradigm, and now it is clear that lactate is important not only as an intermediate in cellular metabolism1 but also as a signaling molecule mediating cellular communications2. Lactate has recently been discovered to modify lysine residues on histones, a post-translational modification called lysine lactylation (Kla or Klac)3. Cellular stress such as hypoxia and bacterial infection induces the production of lactate through glycolysis, which in turn stimulates histone lactylation. This modification on histones not only provides the molecular basis for lactate modulation of gene expression, but also greatly expands biological functions of lactate metabolism. However, in previous analyses by liquid chromatography–tandem mass spectrometry (LC-MS/MS), the mass shift representing lactylation (+72.021 Da) did not offer robust Klac detection and restricted lactylation identifications beyond histones. In this issue of Nature Methods, Wan et al. report the discovery of a signature fragment ion, the cyclic immonium (cycIm) ion, in MS/MS spectra of Klac-containing peptides and used it to confidently identify novel lactylated proteins and modification sites, as well as to discover broader landscape of lactylation beyond histones in the human proteome4.

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Fig. 1: Protein lactylation.

References

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Acknowledgements

This project was funded by NIH grant 1RF1AG064250.

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Authors and Affiliations

  1. Department of Chemistry, Purdue University, West Lafayette, IN, USA

    Xiaofeng Wu & W. Andy Tao

  2. Department of Biochemistry, Purdue University, West Lafayette, IN, USA

    W. Andy Tao

  3. Center for Cancer Research, Purdue University, West Lafayette, IN, USA

    W. Andy Tao

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  1. Xiaofeng Wu
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  2. W. Andy Tao
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Correspondence to Xiaofeng Wu or W. Andy Tao.

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The authors declare no competing interests.

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Wu, X., Tao, W.A. Uncovering ubiquitous protein lactylation. Nat Methods 19, 793–794 (2022). https://doi.org/10.1038/s41592-022-01536-w

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  • DOI: https://doi.org/10.1038/s41592-022-01536-w

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