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Protein metabolism

Grand roles for microproteins

Nature Reviews Molecular Cell Biology volume 26, page 84 (2025)Cite this article

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Across all living species, proteins are involved in most cellular processes and are ultimately the building blocks of cells, tissues and organisms. Identifying and characterizing all the protein-coding genes has therefore been a long-standing quest in the life sciences. A class of small proteins, known as microproteins (or sometimes micropeptides or short/small open reading frames (ORFs)) were initially undetected or dismissed owing to their small size of <100 amino acids. Studies by the Kageyama group (Kondo et al.) and the Couso group (Galindo et al.) were a major milestone in expanding our definitions of what functional proteins could be and do in the context of animal development.

By identifying functional roles for small proteins encoded by short ORFs, these two studies laid the foundation for continued exploration of microproteins. Now, 17 years after these publications, the field is primed with new technologies and perspectives to explore many open questions. For example, thousands of putative microproteins have been identified in animals — how, when, and where are they functional, if at all? And how may altered physiological states, such as cancer, ageing or stressed states, enable ORFs to become transcribed and translated? These questions are linked to the evolution of newly arising or lost small ORFs, and how they may contribute to the evolution of novel cellular processes, states or types.

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References

Original articles

  • Kondo, T. et al. Small peptide regulators of actin-based cell morphogenesis encoded by a polycistronic mRNA. Nat. Cell Biol. 9, 660–665 (2007)

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  • Galindo, M. I. et al. Peptides encoded by short ORFs control development and define a new eukaryotic gene family. PLoS Biol. 5, e106 (2007)

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Acknowledgements

This work is supported by funding from the US National Institutes of Health Eunice Kennedy Shriver Institute for Child Health and Human Development (R00HD105001) to V.A.T. The content is solely the responsibility of the author and does not necessarily represent the official views of the National Institutes of Health.

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  1. Department of Integrative Biology and Physiology, Institute for Society and Genetics, University of California, Los Angeles, CA, USA

    Valerie A. Tornini

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  1. Valerie A. Tornini
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Correspondence to Valerie A. Tornini.

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Tornini, V.A. Grand roles for microproteins. Nat Rev Mol Cell Biol 26, 84 (2025). https://doi.org/10.1038/s41580-024-00806-z

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