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Making single-cell proteomics biologically relevant

Nature Methods volume 20, pages 320–323 (2023)Cite this article

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Recent technological advances in mass spectrometry promise to add single-cell proteomics to the biologist’s toolbox. Here we discuss the current status and what is needed for this exciting technology to lead to biological insight — alone or as a complement to other omics technologies.

As biological researchers, we want to identify rules that characterize a given system. In the past, much of this work has taken place either in vitro in cell culture or in vivo in whole animals or tissues. However, surprisingly often those discoveries hold true only in the chosen experimental conditions. The nascent field of single-cell omics captures the wide range of potential behaviors with various metabolic microenvironments, cell types, and (epi)genetic states. Tremendous developments in RNA sequencing (RNA-seq) technologies have enabled robust measurement of cellular transcriptomes of thousands of single cells1. This has recently been extended into the spatial dimension and, increasingly, to other genomic readouts2. As proteins are in most cases the biological actors in cellular life, an unbiased proteomic dimension would be a logical next addition to the omics arsenal of single-cell biology. However, apart from antibody-based technologies, which typically only cover a small number of predefined protein targets, mass spectrometry (MS)-based proteomics has so far been hampered by enormous technological challenges, mainly in sensitivity and throughput.

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Fig. 1: The dawn of single-cell proteomics.
Fig. 2: Approaching biology with sc-proteomics.

References

  1. Elmentaite, R., Domínguez Conde, C., Yang, L. & Teichmann, S. A. Nat. Rev. Genet. 23, 395–410 (2022).

    Article  CAS  PubMed  Google Scholar 

  2. Deng, Y. et al. Nature 609, 375–383, https://doi.org/10.1038/s41586-022-05094-1 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Milo, R., Jorgensen, P., Moran, U., Weber, G. & Springer, M. Nucleic Acids Res. 38, D750–D753 (2010).

    Article  CAS  PubMed  Google Scholar 

  4. Zhu, Y. et al. Nat. Commun. 9, 882 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Brunner, A.-D. et al. Mol. Syst. Biol. 18, e10798 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Kelly, R. T. Mol. Cell. Proteomics 19, 1739–1748 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Stejskal, K., Op de Beeck, J., Dürnberger, G., Jacobs, P. & Mechtler, K. Anal. Chem. 93, 8704–8710 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Müller, J. B. et al. Nature 582, 592–596 (2020).

    Article  PubMed  Google Scholar 

  9. Sandow, J. J., Infusini, G., Dagley, L. F., Larsen, R. & Webb, A. I. Preprint at bioRxiv https://doi.org/10.1101/657908 (2021).

  10. Ludwig, C. et al. Mol. Syst. Biol. 14, e8126 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  11. Demichev, V., Messner, C. B., Vernardis, S. I., Lilley, K. S. & Ralser, M. Nat. Methods 17, 41–44 (2020).

    Article  CAS  PubMed  Google Scholar 

  12. Bekker-Jensen, D. B. et al. Cell Syst. 4, 587–599.e4 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Meier, F., Geyer, P. E., Virreira Winter, S., Cox, J. & Mann, M. Nat. Methods 15, 440–448 (2018).

    Article  CAS  PubMed  Google Scholar 

  14. Budnik, B., Levy, E., Harmange, G. & Slavov, N. Genome Biol. 19, 161 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Cheung, T. K. et al. Nat. Methods 18, 76–83 (2021).

    Article  CAS  PubMed  Google Scholar 

  16. Ye, Z., Batth, T. S., Rüther, P. & Olsen, J. V. Commun. Biol. 5, 150 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Minogue, C. E. et al. Anal. Chem. 87, 2570–2575 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Derks, J. et al. Nat. Biotechnol. 41, 50–59 (2023).

    Article  CAS  PubMed  Google Scholar 

  19. Griffiths, J. R. et al. J. Am. Soc. Mass Spectrom. 25, 767–777 (2014).

    Article  CAS  PubMed  Google Scholar 

  20. Thielert, M. et al. Preprint at bioRxiv https://doi.org/10.1101/2022.12.02.518917 (2022).

  21. Messner, C. B. et al. Nat. Biotechnol. 39, 846–854 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Mund, A. et al. Nat. Biotechnol. 40, 1231–1240 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Rosenberger, F. A. et al. Preprint at bioRxiv https://doi.org/10.1101/2022.12.03.518957 (2022).

  24. Kühl, I. et al. eLife 6, e30952 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank the members of our single-cell and DVP teams in Munich and Copenhagen for discussions. The authors are supported by grants from the Max Planck Society for the Advancement of Science, Germany, and the European Union’s Horizon 2020 research and innovation program ISLET (No. 874839). F.A.R. is an EMBO postdoctoral fellowship holder (ALTF 399-2021). We thank Juliet Percival (Percival Press, Durham, UK) for the scientific illustrations.

Author information

Author notes

  1. These authors contributed equally: Florian A. Rosenberger, Marvin Thielert.

Authors and Affiliations

  1. Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany

    Florian A. Rosenberger, Marvin Thielert & Matthias Mann

  2. Proteomics Program, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Matthias Mann

Authors
  1. Florian A. Rosenberger
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  2. Marvin Thielert
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Contributions

M.M., M.T. and F.A.R. conceived the original idea. M.M., F.A.R. and M.T. wrote and edited the original draft. F.A.R., M.T. and M.M. conceptualized and guided the illustration process. All authors wrote, edited and gave final approval to the manuscript.

Corresponding author

Correspondence to Matthias Mann.

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Competing interests

M.M. is an indirect shareholder in Evosep Biosystems. The remaining authors declare no competing interests.

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Rosenberger, F.A., Thielert, M. & Mann, M. Making single-cell proteomics biologically relevant. Nat Methods 20, 320–323 (2023). https://doi.org/10.1038/s41592-023-01771-9

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