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Probing condensate microenvironments with a micropeptide killswitch
Yaotian Zhang1,2, Ida Stöppelkamp1,2, Pablo Fernandez-Pernas3
1Max Planck Institute for Molecular Genetics, Berlin, Germany.
Nature
|June 4, 2025
Summary
Scientists developed a novel "killswitch" micropeptide to probe cellular condensates. This tool immobilizes proteins within condensates, revealing their crucial role in cell function and disease processes.
Area of Science:
- Cell Biology
- Biochemistry
- Molecular Biology
Background:
- Biomolecular condensates form distinct subcellular microenvironments.
- Probing condensate microenvironments and their functions is challenging due to limited tools for selective manipulation in living cells.
Purpose of the Study:
- To develop a universal system to probe endogenous biomolecular condensates.
- To demonstrate direct links between condensate microenvironments and biological functions.
Main Methods:
- Development of a non-natural micropeptide (killswitch) and a nanobody-based recruitment system.
- Recruitment of the killswitch to endogenous condensates in human cells, including nucleolar, cancer-related, and viral condensates.
- Assessment of the effects of killswitch-induced protein immobilization on condensate composition, protein mobility, and cellular processes.
Main Results:
- The killswitch successfully immobilized condensate-forming proteins, altering condensate composition and function.
- Targeting the killswitch to nucleoli affected nucleolar composition and ribosomal protein mobility.
- Killswitch recruitment to cancer-specific condensates inhibited leukemia cell proliferation.
- Inhibition of adenoviral particle assembly was observed upon killswitch targeting to viral condensates.
Conclusions:
- The microenvironment within cellular condensates is essential for protein enrichment and mobility.
- The killswitch is a versatile tool for altering condensate material properties and investigating their roles in diverse physiological and pathological processes.

