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Journal Article

Local thermodynamics govern formation and dissolution of Caenorhabditis elegans P granule condensates


Diaz-Delgadillo,  Andrés F.
Max Planck Institute for Evolutionary Biology, Max Planck Society;

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Fritsch, A. W., Diaz-Delgadillo, A. F., Adame-Arana, O., Hoege, C., Mittasch, M., Kreysing, M., et al. (2021). Local thermodynamics govern formation and dissolution of Caenorhabditis elegans P granule condensates. Proceedings of the National Academy of Sciences of the United States of America, 118(37): e2102772118. doi:10.1073/pnas.2102772118.

Cite as: https://hdl.handle.net/21.11116/0000-0009-4821-1
Living cells rely on a continuous flux of energy to spatially organize biochemical processes. It remains unclear whether cells can achieve this spatial organization via thermodynamic principles. Here, we report the striking behavior of a cold-blooded organism that reacts to environmental temperature changes similar to a thermodynamic system at local equilibrium. Our key finding is that protein-rich droplets form and dissolve reversibly with temperature due to changes in the organism’}s entropy. We show that the organism uses a specific molecule to extend droplet stability to the natural temperature range of the organism{’}s habitat. Due to the relevance of such protein droplets for the organism{’}s fertility, our work sheds light on how molecular components could facilitate biological functions via thermodynamic principles.Membraneless compartments, also known as condensates, provide chemically distinct environments and thus spatially organize the cell. A well-studied example of condensates is P granules in the roundworm Caenorhabditis elegans that play an important role in the development of the germline. P granules are RNA-rich protein condensates that share the key properties of liquid droplets such as a spherical shape, the ability to fuse, and fast diffusion of their molecular components. An outstanding question is to what extent phase separation at thermodynamic equilibrium is appropriate to describe the formation of condensates in an active cellular environment. To address this question, we investigate the response of P granule condensates in living cells to temperature changes. We observe that P granules dissolve upon increasing the temperature and recondense upon lowering the temperature in a reversible manner. Strikingly, this temperature response can be captured by in vivo phase diagrams that are well described by a Flory{–Huggins model at thermodynamic equilibrium. This finding is surprising due to active processes in a living cell. To address the impact of such active processes on intracellular phase separation, we discuss temperature heterogeneities. We show that, for typical estimates of the density of active processes, temperature represents a well-defined variable and that mesoscopic volume elements are at local thermodynamic equilibrium. Our findings provide strong evidence that P granule assembly and disassembly are governed by phase separation based on local thermal equilibria where the nonequilibrium nature of the cytoplasm is manifested on larger scales.All study data are included in this article and/or SI Appendix. Previously published data were used for this work [PGL-1 and PGL-3 concentration in early N2 worms from Saha et al. (35) was used to calibrate immunoblots].