Probing condensate microenvironments with a micropeptide killswitch

Yaotian Zhang, Ida Stöppelkamp, Pablo Fernandez-Pernas, Melanie Allram, Matthew Charman, Alexandre P. Magalhaes, Melanie Piedavent-Salomon, Gregor Sommer, Yu-Chieh Sung, Katrina Meyer, Nicholas Grams, Edwin Halko, Shivali Dongre, David Meierhofer, Michal Malszycki, Ibrahim A. Ilik, Tugce Aktas, Matthew L. Kraushar, Nadine Vastenhouw, Matthew D. Weitzman, Florian Grebien, Henri Niskanen () and Denes Hnisz ()
Additional contact information
Yaotian Zhang: Max Planck Institute for Molecular Genetics
Ida Stöppelkamp: Max Planck Institute for Molecular Genetics
Pablo Fernandez-Pernas: University of Veterinary Medicine
Melanie Allram: University of Veterinary Medicine
Matthew Charman: The Children’s Hospital of Philadelphia
Alexandre P. Magalhaes: Max Planck Institute for Molecular Genetics
Melanie Piedavent-Salomon: Max Planck Institute for Molecular Genetics
Gregor Sommer: Max Planck Institute for Molecular Genetics
Yu-Chieh Sung: Max Planck Institute for Molecular Genetics
Katrina Meyer: Max Planck Institute for Molecular Genetics
Nicholas Grams: University of Pennsylvania Perelman School of Medicine
Edwin Halko: The Children’s Hospital of Philadelphia
Shivali Dongre: University of Lausanne
David Meierhofer: Max Planck Institute for Molecular Genetics
Michal Malszycki: Max Planck Institute for Molecular Genetics
Ibrahim A. Ilik: Max Planck Institute for Molecular Genetics
Tugce Aktas: Max Planck Institute for Molecular Genetics
Matthew L. Kraushar: Max Planck Institute for Molecular Genetics
Nadine Vastenhouw: University of Lausanne
Matthew D. Weitzman: The Children’s Hospital of Philadelphia
Florian Grebien: University of Veterinary Medicine
Henri Niskanen: Max Planck Institute for Molecular Genetics
Denes Hnisz: Max Planck Institute for Molecular Genetics

Nature, 2025, vol. 643, issue 8073, 1107-1116

Abstract: Abstract Biomolecular condensates are thought to create subcellular microenvironments that have different physicochemical properties compared with their surrounding nucleoplasm or cytoplasm1–5. However, probing the microenvironments of condensates and their relationship to biological function is a major challenge because tools to selectively manipulate specific condensates in living cells are limited6–9. Here, we develop a non-natural micropeptide (that is, the killswitch) and a nanobody-based recruitment system as a universal approach to probe endogenous condensates, and demonstrate direct links between condensate microenvironments and function in cells. The killswitch is a hydrophobic, aromatic-rich sequence with the ability to self-associate, and has no homology to human proteins. When recruited to endogenous and disease-specific condensates in human cells, the killswitch immobilized condensate-forming proteins, leading to both predicted and unexpected effects. Targeting the killswitch to the nucleolar protein NPM1 altered nucleolar composition and reduced the mobility of a ribosomal protein in nucleoli. Targeting the killswitch to fusion oncoprotein condensates altered condensate compositions and inhibited the proliferation of condensate-driven leukaemia cells. In adenoviral nuclear condensates, the killswitch inhibited partitioning of capsid proteins into condensates and suppressed viral particle assembly. The results suggest that the microenvironment within cellular condensates has an essential contribution to non-stoichiometric enrichment and mobility of effector proteins. The killswitch is a widely applicable tool to alter the material properties of endogenous condensates and, as a consequence, to probe functions of condensates linked to diverse physiological and pathological processes.

Date: 2025
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DOI: 10.1038/s41586-025-09141-5

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