Abstract
Condensed droplets of protein regulate many cellular functions, yet the physiological conditions regulating their formation remain largely unexplored. Increasing our understanding of these mechanisms is paramount, as failure to control condensate formation and dynamics can lead to many diseases. Here, we provide evidence that matrix stiffening promotes biomolecular condensation in vivo. We demonstrate that the extracellular matrix links mechanical cues with the control of glucose metabolism to sorbitol. In turn, sorbitol acts as a natural crowding agent to promote biomolecular condensation. Using in silico simulations and in vitro assays, we establish that variations in the physiological range of sorbitol concentrations, but not glucose concentrations, are sufficient to regulate biomolecular condensates. Accordingly, pharmacological and genetic manipulation of intracellular sorbitol concentration modulates biomolecular condensates in breast cancer—a mechano-dependent disease. We propose that sorbitol is a mechanosensitive metabolite enabling protein condensation to control mechano-regulated cellular functions.
Original language | English (US) |
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Pages (from-to) | 447-464.e20 |
Journal | Cell |
Volume | 188 |
Issue number | 2 |
DOIs | |
State | Published - Jan 23 2025 |
Funding
This platform is supported by the GIS IBiSA, Conseil D\u00E9partemental 06, R\u00E9gion PACA ARC, Cancer\u00F4pole PACA. This work was supported by the French National Research Agency (ANR-18-CE14-0025, ANR-20-CE14-0006, ANR-21-CE44-0036, and ANR-22-CE13-0020), the French National Cancer Institute INCA-PLBIO 21-094, and the foundation ARC pour la recherch\u00E9 sur le cancer PJA20191209291 (to T.B.); the French National Cancer Institute INCA-PLBIO 22-066, the foundation ARC pour la recherche sur le cancer PJA2021050003611, and Cancer\u00F4pole PACA, Emergence grant 2021 (to S.T.); and a grant from the National Institutes of Health (R01GM143334) (to I.B.-S.). I.S.B. acknowledges funding from the Derek Brewer scholarship of Emmanuel College and EPSRC Doctoral Training Programme studentship, number EP/T517847/1. A.R.T. and J.R.E. acknowledge funding from the Ramon y Cajal fellowship (RYC2021-030937-I). J.R.E. acknowledges funding from the Spanish scientific plan and committee for research reference PID2022-136919NA-C33. A.R.T. and R.C.-G. acknowledge funding from the European Research Council (ERC) under the European Union Horizon 2020 research and innovation programme (grant agreement 803326). Atomistic and coarse-grained simulations were performed using resources provided by the Cambridge Tier-2 system operated by the University of Cambridge Research Computing Service (http://www.hpc.cam.ac.uk) funded by EPSRC Tier-2 capital grants EP/P020259/1-CS092, EP/P020259/Su111, and EP/P020259/e829.
Keywords
- LLPS
- biomolecular condensate
- breast cancer
- cell metabolism
- glucose metabolism
- mechanobiology
- phase transition
- sorbitol
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology