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• W3105227545 abstract "Biological liquid–liquid phase separation has gained considerable attention in recent years as a driving force for the assembly of subcellular compartments termed membraneless organelles. The field has made great strides in elucidating the molecular basis of biomolecular phase separation in various disease, stress response, and developmental contexts. Many important biological consequences of such “condensation” are now emerging from in vivo studies. Here we review recent work from our group and others showing that many proteins undergo rapid, reversible condensation in the cellular response to ubiquitous environmental fluctuations such as osmotic changes. We discuss molecular crowding as an important driver of condensation in these responses and suggest that a significant fraction of the proteome is poised to undergo phase separation under physiological conditions. In addition, we review methods currently emerging to visualize, quantify, and modulate the dynamics of intracellular condensates in live cells. Finally, we propose a metaphor for rapid phase separation based on cloud formation, reasoning that our familiar experiences with the readily reversible condensation of water droplets help understand the principle of phase separation. Overall, we provide an account of how biological phase separation supports the highly intertwined relationship between the composition and dynamic internal organization of cells, thus facilitating extremely rapid reorganization in response to internal and external fluctuations. Biological liquid–liquid phase separation has gained considerable attention in recent years as a driving force for the assembly of subcellular compartments termed membraneless organelles. The field has made great strides in elucidating the molecular basis of biomolecular phase separation in various disease, stress response, and developmental contexts. Many important biological consequences of such “condensation” are now emerging from in vivo studies. Here we review recent work from our group and others showing that many proteins undergo rapid, reversible condensation in the cellular response to ubiquitous environmental fluctuations such as osmotic changes. We discuss molecular crowding as an important driver of condensation in these responses and suggest that a significant fraction of the proteome is poised to undergo phase separation under physiological conditions. In addition, we review methods currently emerging to visualize, quantify, and modulate the dynamics of intracellular condensates in live cells. Finally, we propose a metaphor for rapid phase separation based on cloud formation, reasoning that our familiar experiences with the readily reversible condensation of water droplets help understand the principle of phase separation. Overall, we provide an account of how biological phase separation supports the highly intertwined relationship between the composition and dynamic internal organization of cells, thus facilitating extremely rapid reorganization in response to internal and external fluctuations. In eukaryotic cells, the densely packed intracellular environment is compartmentalized to allow specific biochemical reaction pathways to be efficiently regulated in a complex, highly heterogeneous environment where individual catalysts and reactants are present at low concentrations. While membrane-bound organelles have been considered paradigmatic of mechanisms that localize biochemical processes, studies from the past decades have brought increased attention to a more adaptive and dynamic strategy for intracellular spatial organization using “membraneless” organelles (MLOs). These amorphous structures are ubiquitous, are observed across cellular compartments and even in the extracellular space, and are characterized by their lack of a lipid boundary. They are heterogeneous in composition and size, typically ranging from 0.01 to 10 μm, and are subjects of active study owing to their propensity to dynamically assemble and disassemble, priming the cell for rapid responses to intrinsic and extrinsic perturbations (1Gomes E. Shorter J. The molecular language of membraneless organelles.J. Biol. Chem. 2019; 294: 7115-7127Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar, 2Hyman A.A. Weber C.A. Jülicher F. Liquid-liquid phase separation in biology.Annu. Rev. Cell Dev. Biol. 2014; 30: 39-58Crossref PubMed Google Scholar, 3Mitrea D.M. Kriwacki R.W. Phase separation in biology; functional organization of a higher order.Cell Commun. Signal. 2016; 14: 1Crossref PubMed Google Scholar). The prevalence of condensates in all forms of life and the seemingly fundamental rules that govern condensate assembly suggest that these structures and mechanisms may go back to the origins of life itself (4Keating C.D. Aqueous phase separation as a possible route to compartmentalization of biological molecules.Acc. Chem. Res. 2012; 45: 2114-2124Crossref PubMed Scopus (208) Google Scholar, 5Tena-Solsona M. Wanzke C. Riess B. Bausch A.R. Boekhoven J. Self-selection of dissipative assemblies driven by primitive chemical reaction networks.Nat. Commun. 2018; 9: 2044Crossref PubMed Scopus (59) Google Scholar). Since the early days of microscopy and cell biology, cytologists have reported observations of “lifeless bodies,” “granules,” “inclusions,” and other membraneless structures (6Wilson E.B. The cell in development and Inheritance. The Macmillan Co, New York, NY1896: 19-20Google Scholar, 7Wilson E.B. The structure of protoplasm.Science. 1899; 10: 33-45Crossref PubMed Scopus (45) Google Scholar). Despite being observed for over a century, they have come to be extensively studied only in the past decade, largely owing to advances in contemporary technologies that allow probing these structures at unprecedented spatiotemporal resolution, both in vitro and in situ. In addition to technical innovations, our understanding of these mesoscopic structures has been shaped by the metaphors used to describe MLOs over the years. This review aims to provide an overview of these different terminologies and put them in perspective of recent insights into hyperosmotic phase separation (HOPS) of the multimeric proteome. Membraneless structures such as the nucleolus, nuclear speckles, and some RNA–protein (RNP) granules have been studied since the first half of the 20th century, although the earliest reports of such structures go back to the 1800s (8Alberti S. Gladfelter A. Mittag T. Considerations and challenges in studying liquid-liquid phase separation and biomolecular condensates.Cell. 2019; 176: 419-434Abstract Full Text Full Text PDF PubMed Scopus (491) Google Scholar). The most prominent of these structures, the nucleolus, was first described as an “organelle,” in the sense of a distinct compartment with an associated function (9Monty K.J. Litt M. Kay E.R. Dounce A.L. Isolation and properties of liver cell nucleoli.J. Biophys. Biochem. Cytol. 1956; 2: 127-145Crossref PubMed Google Scholar). Thus, the earliest descriptors to signify subcellular compartmentalization were borrowed from canonical membrane-bound organelles and simply denoted observable subcellular organization. While this view provided a framework to relate the observable structure of such compartments with their biochemical properties and functions, it did not provide a way to understand the physical origins of nucleoli. The first decade of the 21st century saw attention turning to the function of various, newly discovered classes of membraneless structures. Structures such as P-bodies, stress granules (SGs), purinosomes, and G-bodies were described as “granules,” “compartments,” or “clusters” (5Tena-Solsona M. Wanzke C. Riess B. Bausch A.R. Boekhoven J. Self-selection of dissipative assemblies driven by primitive chemical reaction networks.Nat. Commun. 2018; 9: 2044Crossref PubMed Scopus (59) Google Scholar, 10Anderson P. Kedersha N. RNA granules.J. Cell Biol. 2006; 172: 803-808Crossref PubMed Scopus (802) Google Scholar, 11Jin M. Fuller G.G. Han T. Yao Y. Alessi A.F. Freeberg M.A. Roach N.P. Moresco J.J. Karnovsky A. Baba M. Yates 3rd, J.R. Gitler A.D. Inoki K. Klionsky D.J. Kim J.K. Glycolytic enzymes coalesce in G bodies under hypoxic stress.Cell Rep. 2017; 20: 895-908Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar), terms that emphasize the appearance of such structures under the light or fluorescence microscope. These terms marked, however, a departure from “organelles”—they did not necessarily have associations with differentiated biological function (12Embryology: The Structure of the Human Spermatozoon. vol. 23. 1885https://archive.org/details/101744400.nlm.nih.gov/page/n73/mode/2upGoogle Scholar). This was closely followed by first reports of the dynamic biophysical properties of these structures. Handwerger et al. (13Handwerger K.E. Cordero J.A. Gall J.G. Cajal bodies, nucleoli, and speckles in the Xenopus oocyte nucleus have a low-density, sponge-like structure.Mol. Biol. Cell. 2005; 16: 202-211Crossref PubMed Scopus (147) Google Scholar) recognized that nuclear condensates, which the authors reported to be “porous” and “sponge-like,” are materially continuous with the nuclear matrix and do not pose a barrier to diffusion, while still being compositionally distinct from the nucleoplasm. Brangwynne et al. (14Brangwynne C.P. Phase transitions and size scaling of membrane-less organelles.J. Cell Biol. 2013; 203: 875-881Crossref PubMed Google Scholar) noted that cytoplasmic RNP “granules are…biophysically similar to the rest of the intracellular fluid, and yet appear to represent a different ‘state’ of cytoplasm, comprised of a locally distinct molecular ensemble”. These observations broadened the inquiry into MLOs to include the study of common principles underlying their origins and revealed several unexpected features, such as liquid-like characteristics, liquid-to-solid transitions, etc. The various contexts in which MLOs are now known to exhibit dynamic fluid properties such as droplet fusion, surface tension, dripping, wetting, and viscoelasticity have been reviewed elsewhere (15Berry J. Brangwynne C.P. Haataja M. Physical principles of intracellular organization via active and passive phase transitions.Rep. Prog. Phys. 2018; 81: 046601Crossref PubMed Google Scholar, 16Hyman A.A. Simons K. Cell biology. Beyond oil and water--phase transitions in cells.Science. 2012; 337: 1047-1049Crossref PubMed Scopus (0) Google Scholar, 17Shin Y. Brangwynne C.P. Liquid phase condensation in cell physiology and disease.Science. 2017; 357eaaf4382Crossref PubMed Scopus (971) Google Scholar, 18Abbondanzieri E.A. Meyer A.S. More than just a phase: the search for membraneless organelles in the bacterial cytoplasm.Curr. Genet. 2019; 65: 691-694Crossref PubMed Scopus (25) Google Scholar). Since the 2010s, the term “membraneless organelle,” originally used to describe the nucleolus, started to be applied in a more general sense to RNP granules and other “assemblies/assemblages” that show fluid-like properties (14Brangwynne C.P. Phase transitions and size scaling of membrane-less organelles.J. Cell Biol. 2013; 203: 875-881Crossref PubMed Google Scholar). This broadening of the term from one specific structure to an entire category of structures similarly marked the start of a unification and ascension of the study of MLOs, whose biological functions were previously underappreciated and considered unrelated. With increasing interest in phase separation as the basis of the formation of MLOs, the introduction of the phrase “biomolecular condensates” in 2017 has helped bridge the gap between physiological in situ observations of such structures and inquiry into their biophysical origins. The term “condensate” explicitly refers to the process of MLO formation and, in doing so, goes beyond the signifier of mere organization connoted by “droplet/MLO” to make a firmer claim about a specific mechanism of formation via phase transition (19Banani S.F. Lee H.O. Hyman A.A. Rosen M.K. Biomolecular condensates: organizers of cellular biochemistry.Nat. Rev. Mol. Cell Biol. 2017; 18: 285-298Crossref PubMed Scopus (1409) Google Scholar, 20Courchaine E.M. Lu A. Neugebauer K.M. Droplet organelles?.EMBO J. 2016; 35: 1603-1612Crossref PubMed Google Scholar). Converging on a consensus of terminology, the field has seen an increase in efforts to elucidate the macromolecular structural and sequence features that promote MLO assembly in vivo and to study the physiological roles of such structures in development, stress response, and disease (21Quiroz F.G. Fiore V.F. Levorse J. Polak L. Wong E. Pasolli H.A. Fuchs E. Liquid-liquid phase separation drives skin barrier formation.Science. 2020; 367eaax9554Crossref PubMed Scopus (15) Google Scholar). Significant attention has been focused on the phase separation processes in pathological contexts. Prominently, toxic protein aggregation such as those formed by β-amyloid peptide (Aβ) and tau proteins in Alzheimer’s disease, TDP-43/FUS in amyotrophic lateral sclerosis (ALS), and huntingtin protein in Huntington’s disease have been studied as archetypical phase separation processes (22Elbaum-Garfinkle S. Matter over mind: liquid phase separation and neurodegeneration.J. Biol. Chem. 2019; 294: 7160-7168Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar, 23Alberti S. Dormann D. Liquid-liquid phase separation in disease.Annu. Rev. Genet. 2019; 53: 171-194Crossref PubMed Scopus (146) Google Scholar, 24de Oliveira G.A.P. Cordeiro Y. Silva J.L. Vieira T. Liquid-liquid phase transitions and amyloid aggregation in proteins related to cancer and neurodegenerative diseases.Adv. Protein Chem. Struct. Biol. 2019; 118: 289-331Crossref PubMed Scopus (17) Google Scholar, 25de Oliveira G.A.P. Petronilho E.C. Pedrote M.M. Marques M.A. Vieira T. Cino E.A. Silva J.L. The status of p53 oligomeric and aggregation states in cancer.Biomolecules. 2020; 10: 548Crossref Scopus (10) Google Scholar, 26Vanderweyde T. Youmans K. Liu-Yesucevitz L. Wolozin B. Role of stress granules and RNA-binding proteins in neurodegeneration: a mini-review.Gerontology. 2013; 59: 524-533Crossref PubMed Scopus (74) Google Scholar, 27Ryan V.H. Fawzi N.L. Physiological, pathological, and targetable membraneless organelles in neurons.Trends Neurosci. 2019; 42: 693-708Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar). In this review, we aim to provide a unifying account of intracellular phase separation in which widespread condensation across the proteome, representing the basal tendency of the intracellular environment, is co-opted to sense and appropriately respond to environmental fluctuations and can go awry in disease. We take a physically motivated view of the cell in which the interior of the cell is poised on the brink of phase separation (7Wilson E.B. The structure of protoplasm.Science. 1899; 10: 33-45Crossref PubMed Scopus (45) Google Scholar, 28Walter H. Brooks D.E. Phase separation in cytoplasm, due to macromolecular crowding, is the basis for microcompartmentation.FEBS Lett. 1995; 361: 135-139Crossref PubMed Scopus (152) Google Scholar, 29Brooks D.E. Can cytoplasm exist without undergoing phase separation?.Int. Rev. Cytol. 2000; 192: 321-330Crossref PubMed Google Scholar). To properly understand the implications of this broadly adaptive cellular behavior, we will first review the theory of phase separation and some important contexts in which cells respond to environmental fluctuations by physicochemical condensation. Biological liquid–liquid phase separation (LLPS) originates from the weak protein–protein, protein–RNA, and RNA-RNA interactions that drive intracellular solutes to partition out of the dilute phase and preferentially into a condensate, the concentrated dense phase. One important tool to study equilibrium phase separation behavior of a solute is the phase diagram (Fig. 1A). A phase diagram is a graphical representation of the thermodynamics of phase separation. It depicts all possible phase states of the system in N-dimensional phase space, where N is the number of external factors that determine the relative contribution of interactions to the free energy of the system (30Goldenfeld N. Lectures on Phase Transitions and the Renormalization Group. Westview Press, Boulder, Colorado1992Google Scholar). Key factors relevant to biological phase transitions include temperature, concentration, valency, and interaction strength. A critical point in this N-dimensional phase space is the threshold beyond which the differences between phases vanish and thus no phase separation is possible, and the system is said to be well mixed. If one factor, say temperature, is fixed at or above its value of the “critical saturation temperature,” phase separation will not occur regardless of the value of all other influencing factors. Biological systems have been observed to show both upper and lower critical saturation temperature (UCST and LCST) behaviors, which determine whether increasing temperature will shift the system out of or into the two-phase region, respectively (31Dignon G.L. Best R.B. Mittal J. Biomolecular phase separation: from molecular driving forces to macroscopic properties.Annu. Rev. Phys. Chem. 2020; 71: 53-75Crossref PubMed Scopus (55) Google Scholar). At any given temperature, the minimal concentration that causes the solute to start undergoing condensation is called the “saturation concentration,” and increasing the concentration further will cause the system to enter the two-phase (“demixed”) region. The effects of isothermal concentration changes and isomolar temperature changes on phase behavior are depicted in Figure 1A, left. Biologically relevant perturbations, in addition to changing component concentrations, may end up reshaping the phase diagram itself, only then allowing the system to undergo phase separation at lower concentrations or temperatures (Fig. 1A, right). Extensive efforts have been dedicated to elucidating the molecular features that drive intracellular phase separation (32Wang J. Choi J.M. Holehouse A.S. Lee H.O. Zhang X. Jahnel M. Maharana S. Lemaitre R. Pozniakovsky A. Drechsel D. Poser I. Pappu R.V. Alberti S. Hyman A.A. A molecular grammar governing the driving forces for phase separation of prion-like RNA binding proteins.Cell. 2018; 174: 688-699.e616Abstract Full Text Full Text PDF PubMed Scopus (480) Google Scholar, 33Dignon G.L. Zheng W. Kim Y.C. Mittal J. Temperature-controlled liquid-liquid phase separation of disordered proteins.ACS Cent. Sci. 2019; 5: 821-830Crossref PubMed Scopus (0) Google Scholar). The most general requirement is multivalency, which allows molecules to form large assemblies via multiple intermolecular contacts. Within protein–protein interfaces, arginine–glycine–glycine/arginine–glycine motifs (34Thandapani P. O'Connor T.R. Bailey T.L. Richard S. Defining the RGG/RG motif.Mol. Cell. 2013; 50: 613-623Abstract Full Text Full Text PDF PubMed Scopus (293) Google Scholar), π–π (35Vernon R.M. Chong P.A. Tsang B. Kim T.H. Bah A. Farber P. Lin H. Forman-Kay J.D. Pi-Pi contacts are an overlooked protein feature relevant to phase separation.Elife. 2018; 7e31486Crossref PubMed Google Scholar), cation–π, and charge–charge interactions, among others, have been shown to drive protein phase separation (36Lin Y.H. Forman-Kay J.D. Chan H.S. Theories for sequence-dependent phase behaviors of biomolecular condensates.Biochemistry. 2018; 57: 2499-2508Crossref PubMed Scopus (82) Google Scholar, 37Posey A.E. Holehouse A.S. Pappu R.V. Phase separation of intrinsically disordered proteins.Methods Enzymol. 2018; 611: 1-30Crossref PubMed Scopus (54) Google Scholar, 38Protter D.S.W. Rao B.S. Van Treeck B. Lin Y. Mizoue L. Rosen M.K. Parker R. Intrinsically disordered regions can contribute promiscuous interactions to RNP granule assembly.Cell Rep. 2018; 22: 1401-1412Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar, 39Feng Z. Chen X. Wu X. Zhang M. Formation of biological condensates via phase separation: characteristics, analytical methods, and physiological implications.J. Biol. Chem. 2019; 294: 14823-14835Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, 40Turoverov K.K. Kuznetsova I.M. Fonin A.V. Darling A.L. Zaslavsky B.Y. Uversky V.N. Stochasticity of biological soft matter: emerging concepts in intrinsically disordered proteins and biological phase separation.Trends Biochem. Sci. 2019; 44: 716-728Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar). These interactions stimulate the higher-order assembly of prion-like domains in protein misfolding diseases (32Wang J. Choi J.M. Holehouse A.S. Lee H.O. Zhang X. Jahnel M. Maharana S. Lemaitre R. Pozniakovsky A. Drechsel D. Poser I. Pappu R.V. Alberti S. Hyman A.A. A molecular grammar governing the driving forces for phase separation of prion-like RNA binding proteins.Cell. 2018; 174: 688-699.e616Abstract Full Text Full Text PDF PubMed Scopus (480) Google Scholar), together with disordered regions and RNA-scaffolded assembly (41Shin Y. Berry J. Pannucci N. Haataja M.P. Toettcher J.E. Brangwynne C.P. Spatiotemporal control of intracellular phase transitions using light-activated optoDroplets.Cell. 2017; 168: 159-171.e114Abstract Full Text Full Text PDF PubMed Scopus (283) Google Scholar, 42Sanders D.W. Kedersha N. Lee D.S.W. Strom A.R. Drake V. Riback J.A. Bracha D. Eeftens J.M. Iwanicki A. Wang A. Wei M.T. Whitney G. Lyons S.M. Anderson P. Jacobs W.M. et al.Competing protein-RNA interaction networks control multiphase intracellular organization.Cell. 2020; 181: 306-324.e328Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar, 43Yang P. Mathieu C. Kolaitis R.M. Zhang P. Messing J. Yurtsever U. Yang Z. Wu J. Li Y. Pan Q. Yu J. Martin E.W. Mittag T. Kim H.J. Taylor J.P. G3BP1 is a tunable switch that triggers phase separation to assemble stress granules.Cell. 2020; 181: 325-345.e328Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar). Additionally, structured protein domains are now emerging as mediators of widespread intracellular phase separation under conditions of high concentration and molecular crowding (44Zhou H.X. Nguemaha V. Mazarakos K. Qin S. Why do disordered and structured proteins behave differently in phase separation?.Trends Biochem. Sci. 2018; 43: 499-516Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar, 45Schmidt A. Gao G. Little S.R. Jalihal A.P. Walter N.G. Following the messenger: recent innovations in live cell single molecule fluorescence imaging.Wiley Interdiscip. Rev. RNA. 2020; 11e1587Crossref PubMed Scopus (0) Google Scholar). Altered expression of RNA and protein components therefore can drastically influence both condensation and phase behavior itself (Fig. 1B). Disrupting any of these key interactions driving phase separation is expected to interfere with the phase separation potential of a system. Consistent with this expectation, posttranslational modifications such as phosphorylation and methylation have been found to modulate condensation responses (46Rai A.K. Chen J.X. Selbach M. Pelkmans L. Kinase-controlled phase transition of membraneless organelles in mitosis.Nature. 2018; 559: 211-216Crossref PubMed Scopus (133) Google Scholar, 47Bah A. Forman-Kay J.D. Modulation of intrinsically disordered protein function by post-translational modifications.J. Biol. Chem. 2016; 291: 6696-6705Abstract Full Text Full Text PDF PubMed Scopus (221) Google Scholar, 48Owen I. Shewmaker F. The role of post-translational modifications in the phase transitions of intrinsically disordered proteins.Int. J. Mol. Sci. 2019; 20: 5501Crossref PubMed Scopus (7) Google Scholar, 49Jalihal A.P. Pitchiaya S. Xiao L. Bawa P. Jiang X. Bedi K. Parolia A. Cieslik M. Ljungman M. Chinnaiyan A.M. Walter N.G. Multivalent proteins rapidly and reversibly phase-separate upon osmotic cell volume change.Mol. Cell. 2020; 79: 978-990.e975Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar) (Fig. 1B). The effects of phosphorylation in particular can be dramatic so that, for example, the kinase DYRK3, which prevents condensation of splicing factors in M phase, has been appropriately referred to as a “dissolvase” (46Rai A.K. Chen J.X. Selbach M. Pelkmans L. Kinase-controlled phase transition of membraneless organelles in mitosis.Nature. 2018; 559: 211-216Crossref PubMed Scopus (133) Google Scholar). Similarly, SG assembly in response to various stresses depends on phosphorylation of G3BP and PABP (50Kedersha N. Ivanov P. Anderson P. Stress granules and cell signaling: more than just a passing phase?.Trends Biochem. Sci. 2013; 38: 494-506Abstract Full Text Full Text PDF PubMed Scopus (343) Google Scholar). Accordingly, posttranslational modifications are emerging as key modulators of phase separation (48Owen I. Shewmaker F. The role of post-translational modifications in the phase transitions of intrinsically disordered proteins.Int. J. Mol. Sci. 2019; 20: 5501Crossref PubMed Scopus (7) Google Scholar, 51Hofweber M. Dormann D. Friend or foe-post-translational modifications as regulators of phase separation and RNP granule dynamics.J. Biol. Chem. 2019; 294: 7137-7150Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar, 52Kim T.H. Tsang B. Vernon R.M. Sonenberg N. Kay L.E. Forman-Kay J.D. Phospho-dependent phase separation of FMRP and CAPRIN1 recapitulates regulation of translation and deadenylation.Science. 2019; 365: 825-829Crossref PubMed Scopus (81) Google Scholar). A perturbation of biological interest is concentration change arising from altered gene expression or nucleocytoplasmic trafficking, processes commonly associated with developmental changes, signaling, and disease (Fig. 1B). While the impact of changing concentration on phase separation by itself is straightforward to study with purified recombinant proteins, there are important caveats to be considered when relating such in vitro observations to intracellular concentration changes. Notably, any condition that alters intracellular concentration entails simultaneous changes in multiple factors that influence the phase separation outcome. Hyperosmotic compression, for instance, leads to a decrease in diffusion rates of large macromolecules, an increase in molecular crowding, and possible ionic imbalances in addition to changes in effective concentrations of biomolecules; we elaborate on this multiplicity of changes associated with HOPS later in the text. These effects are similar to changes that have been reported in bacteria, yeasts, and protists in response to glucose starvation, in which volume change causes a fluid-to-glass transition of the intracellular space, simultaneously impacting diffusivity as well as intracellular pH (53Joyner R.P. Tang J.H. Helenius J. Dultz E. Brune C. Holt L.J. Huet S. Muller D.J. Weis K. A glucose-starvation response regulates the diffusion of macromolecules.Elife. 2016; 5e09376Crossref PubMed Scopus (0) Google Scholar, 54Isom D.G. Page S.C. Collins L.B. Kapolka N.J. Taghon G.J. Dohlman H.G. Coordinated regulation of intracellular pH by two glucose-sensing pathways in yeast.J. Biol. Chem. 2018; 293: 2318-2329Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar, 55Munder M.C. Midtvedt D. Franzmann T. Nüske E. Otto O. Herbig M. Ulbricht E. Müller P. Taubenberger A. Maharana S. Malinovska L. Richter D. Guck J. Zaburdaev V. Alberti S. A pH-driven transition of the cytoplasm from a fluid- to a solid-like state promotes entry into dormancy.Elife. 2016; 5e09347Crossref PubMed Scopus (176) Google Scholar). In both these perturbations, the phase separation outcome depends on the compound effects of each of these factors in reshaping the phase boundaries and altering the saturation concentration (Fig. 1, A–B). Furthermore, such perturbations typically represent dynamic nonequilibrium situations within a complex matrix of competing cellular interaction partners (56Walter N.G. Biological pathway specificity in the cell-does molecular diversity matter?.Bioessays. 2019; 41e1800244Crossref PubMed Scopus (5) Google Scholar), which adds to the complexity of studying intracellular phase separation (57Milin A.N. Deniz A.A. Reentrant phase transitions and non-equilibrium dynamics in membraneless organelles.Biochemistry. 2018; 57: 2470-2477Crossref PubMed Scopus (32) Google Scholar, 58Hondele M. Heinrich S. De Los Rios P. Weis K. Membraneless organelles: phasing out of equilibrium.Emerg. Top. Life Sci. 2020; 4: 331-342PubMed Google Scholar). Inside cells, condensates show several distinct characteristics and behaviors. Different classes of condensates show physical associations with each other that can be important for seeding condensates. Prominently, P-bodies are thought to seed SGs while sharing components with them (42Sanders D.W. Kedersha N. Lee D.S.W. Strom A.R. Drake V. Riback J.A. Bracha D. Eeftens J.M. Iwanicki A. Wang A. Wei M.T. Whitney G. Lyons S.M. Anderson P. Jacobs W.M. et al.Competing protein-RNA interaction networks control multiphase intracellular organization.Cell. 2020; 181: 306-324.e328Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar). Many MLOs have been shown to have ultrastructures, where each condensate often contains a “core” and a “shell” of distinct compositions or subcompartments that differ in material properties (59Boeynaems S. Alberti S. Fawzi N.L. Mittag T. Polymenidou M. Rousseau F. Schymkowitz J. Shorter J. Wolozin B. Van Den Bosch L. Tompa P. Fuxreiter M. Protein phase separation: a new phase in cell biology.Trends Cell Biol. 2018; 28: 420-435Abstract Full Text Full Text PDF PubMed Scopus (603) Google Scholar, 60Boeynaems S. Holehouse A.S. Weinhardt V. Kovacs D. Van Lindt J. Larabell C. Van Den Bosch L. Das R. Tompa P.S. Pappu R.V. Gitler A.D. Spontaneous driving forces give rise to pro" @default.
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• W3105227545 date "2021-01-01" @default.
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• W3105227545 title "Hyperosmotic phase separation: Condensates beyond inclusions, granules and organelles" @default.
• W3105227545 cites W1499182201 @default.
• W3105227545 cites W1517319742 @default.
• W3105227545 cites W1952608303 @default.
• W3105227545 cites W1967920493 @default.
• W3105227545 cites W1970157213 @default.
• W3105227545 cites W1977504104 @default.
• W3105227545 cites W1985681646 @default.
• W3105227545 cites W1988517764 @default.
• W3105227545 cites W1999119928 @default.
• W3105227545 cites W2000219572 @default.
• W3105227545 cites W2007400675 @default.
• W3105227545 cites W2007817196 @default.
• W3105227545 cites W2016906437 @default.
• W3105227545 cites W2018041998 @default.
• W3105227545 cites W2030473151 @default.
• W3105227545 cites W2032469042 @default.
• W3105227545 cites W2036735052 @default.
• W3105227545 cites W2039687911 @default.
• W3105227545 cites W2043021835 @default.
• W3105227545 cites W2049345986 @default.
• W3105227545 cites W2051168928 @default.
• W3105227545 cites W2051822822 @default.
• W3105227545 cites W2054543531 @default.
• W3105227545 cites W2054670584 @default.
• W3105227545 cites W2054752603 @default.
• W3105227545 cites W2055045552 @default.
• W3105227545 cites W2063534825 @default.
• W3105227545 cites W2077502289 @default.
• W3105227545 cites W2079712877 @default.
• W3105227545 cites W2080320477 @default.
• W3105227545 cites W2081311128 @default.
• W3105227545 cites W2091009518 @default.
• W3105227545 cites W2101627628 @default.
• W3105227545 cites W2106046434 @default.
• W3105227545 cites W2120156669 @default.
• W3105227545 cites W2123659736 @default.
• W3105227545 cites W2139066576 @default.
• W3105227545 cites W2146926661 @default.
• W3105227545 cites W2165360511 @default.
• W3105227545 cites W2222857089 @default.
• W3105227545 cites W2300545781 @default.
• W3105227545 cites W2307399619 @default.
• W3105227545 cites W2312179720 @default.
• W3105227545 cites W2331441703 @default.
• W3105227545 cites W2335345046 @default.
• W3105227545 cites W2338988561 @default.
• W3105227545 cites W2402791934 @default.
• W3105227545 cites W2409577334 @default.
• W3105227545 cites W2467565876 @default.
• W3105227545 cites W2518959324 @default.
• W3105227545 cites W2522982067 @default.
• W3105227545 cites W2566521622 @default.
• W3105227545 cites W2590568317 @default.
• W3105227545 cites W2625742743 @default.
• W3105227545 cites W2649090908 @default.
• W3105227545 cites W2697742764 @default.
• W3105227545 cites W2738634672 @default.
• W3105227545 cites W2756821926 @default.
• W3105227545 cites W2769039165 @default.
• W3105227545 cites W2781193336 @default.
• W3105227545 cites W2784297130 @default.
• W3105227545 cites W2786469974 @default.
• W3105227545 cites W2792436658 @default.
• W3105227545 cites W2793035161 @default.
• W3105227545 cites W2794654572 @default.
• W3105227545 cites W2802429563 @default.
• W3105227545 cites W2802667264 @default.
• W3105227545 cites W2803795590 @default.
• W3105227545 cites W2803875145 @default.
• W3105227545 cites W2809092342 @default.
• W3105227545 cites W2810246680 @default.
• W3105227545 cites W2810866092 @default.
• W3105227545 cites W2874653366 @default.
• W3105227545 cites W2884082692 @default.
• W3105227545 cites W2898560457 @default.
• W3105227545 cites W2898777420 @default.
• W3105227545 cites W2901758876 @default.
• W3105227545 cites W2902026154 @default.
• W3105227545 cites W2903264039 @default.
• W3105227545 cites W2905220927 @default.
• W3105227545 cites W2906593639 @default.
• W3105227545 cites W2907972520 @default.
• W3105227545 cites W2908060926 @default.
• W3105227545 cites W2909378020 @default.
• W3105227545 cites W2910213537 @default.
• W3105227545 cites W2914907359 @default.
• W3105227545 cites W2921134191 @default.

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