Probing condensate microenvironments with a micropeptide killswitch
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| Title: | Probing condensate microenvironments with a micropeptide killswitch |
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| Authors: | 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, Denes Hnisz |
| Source: | Nature Nature, vol. 643, no. 8073, pp. 1107-1116 |
| Publisher Information: | Springer Science and Business Media LLC, 2025. |
| Publication Year: | 2025 |
| Subject Terms: | Cell biology, Nuclear organization, Mechanisms of disease, Biowissenschaften, Biologie, Humans, Nucleophosmin, Peptides/chemistry, Peptides/metabolism, Biomolecular Condensates/metabolism, Biomolecular Condensates/chemistry, Cell Nucleolus/metabolism, Cell Nucleolus/chemistry, Single-Domain Antibodies/immunology, Single-Domain Antibodies/metabolism, Single-Domain Antibodies/chemistry, Nuclear Proteins/metabolism, Capsid Proteins/metabolism, Cell Proliferation/drug effects, Cellular Microenvironment, Cell Line, Tumor, Ribosomal Proteins/metabolism, Leukemia/pathology, Leukemia/metabolism, Hydrophobic and Hydrophilic Interactions, Article, Imaging |
| Description: | 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. |
| Document Type: | Article Other literature type |
| File Description: | application/pdf |
| Language: | English |
| ISSN: | 1476-4687 0028-0836 |
| DOI: | 10.1038/s41586-025-09141-5 |
| DOI: | 10.17169/refubium-48629 |
| Access URL: | https://serval.unil.ch/notice/serval:BIB_E354BC5C82D1 http://nbn-resolving.org/urn/resolver.pl?urn=urn:nbn:ch:serval-BIB_E354BC5C82D11 https://serval.unil.ch/resource/serval:BIB_E354BC5C82D1.P001/REF.pdf https://refubium.fu-berlin.de/handle/fub188/48906 https://doi.org/10.17169/refubium-48629 https://doi.org/10.1038/s41586-025-09141-5 |
| Rights: | CC BY |
| Accession Number: | edsair.doi.dedup.....cdcb5937c7f08264331ef8d67163b5ed |
| Database: | OpenAIRE |
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Nájsť tento článok vo Web of Science | 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. |
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| ISSN: | 14764687 00280836 |
| DOI: | 10.1038/s41586-025-09141-5 |