Abstract
Biomolecular condensates are membraneless intracellular assemblies that often form via liquid−liquid phase separation and have the ability to concentrate biopolymers. Research over the past 10 years has revealed that condensates play fundamental roles in cellular organization and physiology, and our understanding of the molecular principles, components and forces underlying their formation has substantially increased. Condensate assembly is tightly regulated in the intracellular environment, and failure to control condensate properties, formation and dissolution can lead to protein misfolding and aggregation, which are often the cause of ageing-associated diseases. In this Review, we describe the mechanisms and regulation of condensate assembly and dissolution, highlight recent advances in understanding the role of biomolecular condensates in ageing and disease, and discuss how cellular stress, ageing-related loss of homeostasis and a decline in protein quality control may contribute to the formation of aberrant, disease-causing condensates. Our improved understanding of condensate pathology provides a promising path for the treatment of protein aggregation diseases.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Banani, S. F., Lee, H. O., Hyman, A. A. & Rosen, M. K. Biomolecular condensates: organizers of cellular biochemistry. Nat. Rev. Mol. Cell Biol. 18, 285–298 (2017).
Shin, Y. & Brangwynne, C. P. Liquid phase condensation in cell physiology and disease. Science 357, eaaf4382 (2017).
Alberti, S., Gladfelter, A. & Mittag, T. Considerations and challenges in studying liquid-liquid phase separation and biomolecular condensates. Cell 176, 419–434 (2019).
Protter, D. S. W. & Parker, R. Principles and properties of stress granules. Trends Cell Biol. 26, 668–679 (2016).
Panas, M. D., Ivanov, P. & Anderson, P. Mechanistic insights into mammalian stress granule dynamics. J. Cell Biol. 215, 313–323 (2016).
Alberti, S. & Dormann, D. Liquid–liquid phase separation in disease. Annu. Rev. Genet. 53, 171–194 (2019).
Snead, W. T. & Gladfelter, A. S. The control centers of biomolecular phase separation: how membrane surfaces, PTMs, and active processes regulate condensation. Mol. Cell 76, 295–305 (2019).
Hipp, M. S., Kasturi, P. & Hartl, F. U. The proteostasis network and its decline in ageing. Nat. Rev. Mol. Cell Biol. 20, 421–435 (2019).
Hyman, A. A., Weber, C. A. & Jülicher, F. Liquid-liquid phase separation in biology. Annu. Rev. Cell Dev. Biol. 30, 39–58 (2014).
Case, L. B., Zhang, X., Ditlev, J. A. & Rosen, M. K. Stoichiometry controls activity of phase-separated clusters of actin signaling proteins. Science 363, 1093–1097 (2019).
Franzmann, T. M. et al. Phase separation of a yeast prion protein promotes cellular fitness. Science 359, eaao5654 (2018).
Klosin, A. et al. Phase separation provides a mechanism to reduce noise in cells. Science 367, 464–468 (2020).
Riback, J. A. et al. Stress-triggered phase separation is an adaptive, evolutionarily tuned response. Cell 168, 1028–1040.e19 (2017).
Shin, Y. et al. Liquid nuclear condensates mechanically sense and restructure the genome. Cell 175, 1481–1491.e13 (2018).
Bienz, M. Head-to-tail polymerization in the assembly of biomolecular condensates. Cell 182, 799–811 (2020).
Wu, H. & Fuxreiter, M. The Structure and dynamics of higher-order assemblies: amyloids, signalosomes, and granules. Cell 165, 1055–1066 (2016).
McSwiggen, D. T., Mir, M., Darzacq, X. & Tjian, R. Evaluating phase separation in live cells: diagnosis, caveats, and functional consequences. Genes Dev. 33, 1619–1634 (2019).
Holehouse, A. S. & Pappu, R. V. Functional implications of intracellular phase transitions. Biochemistry https://doi.org/10.1021/acs.biochem.7b01136 (2018).
Lyon, A. S., Peeples, W. B. & Rosen, M. K. A framework for understanding the functions of biomolecular condensates across scales. Nat. Rev. Mol. Cell Biol. https://doi.org/10.1038/s41580-020-00303-z (2020).
Molliex, A. et al. Phase separation by low complexity domains promotes stress granule assembly and drives pathological fibrillization. Cell 163, 123–133 (2015). Molliex et al. find that hnRNPA1 assembles into liquid droplets by phase separation, which then age into a more solid-like state with time.
Patel, A. et al. A liquid-to-solid phase transition of the ALS protein FUS accelerated by disease mutation. Cell 162, 1066–1077 (2015). Patel et al. report that FUS assembles into liquid droplets by phase separation, which then age into a more solid-like state with time.
Alberti, S. & Hyman, A. A. Are aberrant phase transitions a driver of cellular aging? Bioessays 38, 959–968 (2016).
Murakami, T. et al. ALS/FTD mutation-induced phase transition of FUS liquid droplets and reversible hydrogels into irreversible hydrogels impairs RNP granule function. Neuron 88, 678–690 (2015).
Li, P. et al. Phase transitions in the assembly of multivalent signalling proteins. Nature 483, 336–340 (2012).
Zhou, H.-X., Nguemaha, V., Mazarakos, K. & Qin, S. Why do disordered and structured proteins behave differently in phase separation? Trends Biochem. Sci. 43, 499–516 (2018).
Nott, T. J. et al. Phase transition of a disordered nuage protein generates environmentally responsive membraneless organelles. Mol. Cell 57, 936–947 (2015).
Wang, J. et al. A molecular grammar governing the driving forces for phase separation of prion-like RNA binding proteins. Cell 174, 688–699.e16 (2018). The study by Wang et al. dissects the molecular grammar of FUS phase separation and condensate ageing.
Choi, J.-M., Holehouse, A. S. & Pappu, R. V. Physical principles underlying the complex biology of intracellular phase transitions. Annu. Rev. Biophys. 49, 107–133 (2020).
Semenov, A. N. & Rubinstein, M. Thermoreversible gelation in solutions of associative polymers. 1. Statics. Macromolecules 31, 1373–1385 (1998).
Roden, C. & Gladfelter, A. S. RNA contributions to the form and function of biomolecular condensates. Nat. Rev. Mol. Cell Biol. https://doi.org/10.1038/s41580-020-0264-6 (2020).
Riback, J. A. et al. Composition-dependent thermodynamics of intracellular phase separation. Nature 581, 209–214 (2020).
Banani, S. F. et al. Compositional control of phase-separated cellular bodies. Cell 166, 651–663 (2016).
Langeberg, L. K. & Scott, J. D. Signalling scaffolds and local organization of cellular behaviour. Nat. Rev. Mol. Cell Biol. 16, 232–244 (2015).
Ditlev, J. A., Case, L. B. & Rosen, M. K. Who’s in and who’s out-compositional control of biomolecular condensates. J. Mol. Biol. 430, 4666–4684 (2018).
Guillén-Boixet, J. et al. RNA-induced conformational switching and clustering of G3BP drive stress granule assembly by condensation. Cell 181, 346–361.e17 (2020).
Yang, P. et al. G3BP1 is a tunable switch that triggers phase separation to assemble stress granules. Cell 181, 325–345.e28 (2020).
Sanders, D. W. et al. Competing protein-RNA interaction networks control multiphase intracellular organization. Cell 181, 306–324.e28 (2020).
Falahati, H. & Wieschaus, E. Independent active and thermodynamic processes govern the nucleolus assembly in vivo. Proc. Natl Acad. Sci. USA 114, 1335–1340 (2017).
Su, X. et al. Phase separation of signaling molecules promotes T cell receptor signal transduction. Science 352, 595–599 (2016).
Monahan, Z. et al. Phosphorylation of the FUS low-complexity domain disrupts phase separation, aggregation, and toxicity. EMBO J. 36, 2951–2967 (2017).
Hofweber, M. et al. Phase separation of FUS is suppressed by its nuclear import receptor and arginine methylation. Cell 173, 706–719.e13 (2018). In this study, Hofweber et al. show that nuclear import receptors can regulate the phase-separation behaviour of FUS.
Qamar, S. et al. FUS phase separation is modulated by a molecular chaperone and methylation of arginine cation-π interactions. Cell 173, 720–734.e15 (2018).
Pavitt, G. D. eIF2B, a mediator of general and gene-specific translational control. Biochem. Soc. Trans. 33, 1487–1492 (2005).
Anderson, P. & Kedersha, N. Visibly stressed: the role of eIF2, TIA-1, and stress granules in protein translation. Cell Stress. Chaperones 7, 213–221 (2002).
Banerjee, P. R., Milin, A. N., Moosa, M. M., Onuchic, P. L. & Deniz, A. A. Reentrant phase transition drives dynamic substructure formation in ribonucleoprotein droplets. Angew. Chem. Int. Ed. Engl. 56, 11354–11359 (2017).
Maharana, S. et al. RNA buffers the phase separation behavior of prion-like RNA binding proteins. Science 360, 918–921 (2018). Maharana et al. find that RNA can buffer the phase separation behaviour of disease-causing RNA-binding proteins such as FUS, hnRNPA1 and TDP43.
Patel, A. et al. ATP as a biological hydrotrope. Science 356, 753–756 (2017).
Hayes, M. H., Peuchen, E. H., Dovichi, N. J. & Weeks, D. L. Dual roles for ATP in the regulation of phase separated protein aggregates in Xenopus oocyte nucleoli. eLife 7, e35224 (2018).
Harmon, T. S., Holehouse, A. S., Rosen, M. K. & Pappu, R. V. Intrinsically disordered linkers determine the interplay between phase separation and gelation in multivalent proteins. eLife 6, e30294 (2017).
Iserman, C. et al. Condensation of Ded1p promotes a translational switch from housekeeping to stress protein production. Cell 181, 818–831.e19 (2020).
Jawerth, L. et al. Protein condensates as aging maxwell fluids. Science 370, 1317–1323 (2020).
Roberts, S., Dzuricky, M. & Chilkoti, A. Elastin-like polypeptides as models of intrinsically disordered proteins. FEBS Lett. 589 (19 Pt A), 2477–2486 (2015).
Parry, B. R. et al. The bacterial cytoplasm has glass-like properties and is fluidized by metabolic activity. Cell 156, 183–194 (2014).
Iadanza, M. G., Jackson, M. P., Hewitt, E. W., Ranson, N. A. & Radford, S. E. A new era for understanding amyloid structures and disease. Nat. Rev. Mol. Cell Biol. 19, 755–773 (2018).
Murthy, A. C. et al. Molecular interactions underlying liquid-liquid phase separation of the FUS low-complexity domain. Nat. Struct. Mol. Biol. 26, 637–648 (2019).
Burke, K. A., Janke, A. M., Rhine, C. L. & Fawzi, N. L. Residue-by-residue view of in vitro FUS granules that bind the C-terminal domain of RNA polymerase II. Mol. Cell 60, 231–241 (2015).
Mackenzie, I. R. et al. TIA1 mutations in amyotrophic lateral sclerosis and frontotemporal dementia promote phase separation and alter stress granule dynamics. Neuron 95, 808–816.e9 (2017).
Conicella, A. E., Zerze, G. H., Mittal, J. & Fawzi, N. L. ALS mutations disrupt phase separation mediated by α-helical structure in the TDP-43 low-complexity C-terminal domain. Structure 24, 1537–1549 (2016).
Murray, D. T. et al. Structure of FUS protein fibrils and its relevance to self-assembly and phase separation of low-complexity domains. Cell 171, 615–627.e16 (2017).
Ruckenstein, E. & Shulgin, I. L. Effect of salts and organic additives on the solubility of proteins in aqueous solutions. Adv. Colloid Interface Sci. 123-126, 97–103 (2006).
Piazza, R. Protein interactions and association: an open challenge for colloid science. Curr. Opin. Colloid Interface Sci. 8, 515–522 (2004).
Saha, S. et al. Polar positioning of phase-separated liquid compartments in cells regulated by an mRNA competition mechanism. Cell 166, 1572–1584.e16 (2016).
Serio, T. R. et al. Nucleated conformational conversion and the replication of conformational information by a prion determinant. Science 289, 1317–1321 (2000).
Chatani, E. & Yamamoto, N. Recent progress on understanding the mechanisms of amyloid nucleation. Biophys. Rev. 10, 527–534 (2018).
Jarosz, D. F. & Khurana, V. Specification of physiologic and disease states by distinct proteins and protein conformations. Cell 171, 1001–1014 (2017).
Hughes, M. P. et al. Atomic structures of low-complexity protein segments reveal kinked β sheets that assemble networks. Science 359, 698–701 (2018).
Kato, M. et al. Cell-free formation of RNA granules: low complexity sequence domains form dynamic fibers within hydrogels. Cell 149, 753–767 (2012). Kato et al. report that low complexity domains in RNA-binding proteins can assemble into gels through amyloid-like interactions.
Luo, F. et al. Atomic structures of FUS LC domain segments reveal bases for reversible amyloid fibril formation. Nat. Struct. Mol. Biol. 25, 341–346 (2018).
Kato, M. & McKnight, S. L. A solid-state conceptualization of information transfer from gene to message to protein. Annu. Rev. Biochem. 87, 351–390 (2018).
Peran, I. & Mittag, T. Molecular structure in biomolecular condensates. Curr. Opin. Struct. Biol. 60, 17–26 (2019).
Kato, M. & McKnight, S. L. Cross-β polymerization of low complexity sequence domains. Cold Spring Harb. Perspect. Biol. 9, a023598 (2017).
Murthy, A. C. & Fawzi, N. L. The (un)structural biology of biomolecular liquid-liquid phase separation using NMR spectroscopy. J. Biol. Chem. 295, 2375–2384 (2020).
Breydo, L. & Uversky, V. N. Structural, morphological, and functional diversity of amyloid oligomers. FEBS Lett. 589, 2640–2648 (2015).
Bemporad, F. & Chiti, F. Protein misfolded oligomers: experimental approaches, mechanism of formation, and structure-toxicity relationships. Chem. Biol. 19, 315–327 (2012).
Michaels, T. C. T. et al. Author correction: dynamics of oligomer populations formed during the aggregation of Alzheimer’s Aβ42 peptide. Nat. Chem. 12, 497 (2020).
Morel, B., Carrasco, M. P., Jurado, S., Marco, C. & Conejero-Lara, F. Dynamic micellar oligomers of amyloid beta peptides play a crucial role in their aggregation mechanisms. Phys. Chem. Chem. Phys. 20, 20597–20614 (2018).
Edwin, N. J., Hammer, R. P., McCarley, R. L. & Russo, P. S. Reversibility of β-amyloid self-assembly: effects of pH and added salts assessed by fluorescence photobleaching recovery. Biomacromolecules 11, 341–347 (2010).
Babinchak, W. M. et al. The role of liquid-liquid phase separation in aggregation of the TDP-43 low complexity domain. J. Biol. Chem. 294, 6306–6317 (2019).
Ray, S. et al. α-Synuclein aggregation nucleates through liquid-liquid phase separation. Nat. Chem. 12, 705–716 (2020). Ray et al. show that the disease-associated protein α-synuclein can assemble into liquid droplets by phase separation.
Wegmann, S. et al. Tau protein liquid–liquid phase separation can initiate tau aggregation. EMBO J. 37, e98049 (2018).
Ambadipudi, S., Biernat, J., Riedel, D., Mandelkow, E. & Zweckstetter, M. Liquid-liquid phase separation of the microtubule-binding repeats of the Alzheimer-related protein Tau. Nat. Commun. 8, 275 (2017). The studies by Wegmann et al. and Ambadipudi et al. indicate that the disease-associated protein Tau can assemble into liquid droplets by phase separation.
Franzmann, T. M. & Alberti, S. Protein phase separation as a stress survival strategy. Cold Spring Harb. Perspect. Biol. 11, a034058 (2019).
Kroschwald, S. et al. Different material states of Pub1 condensates define distinct modes of stress adaptation and recovery. Cell Rep. 23, 3327–3339 (2018).
Majumdar, A., Dogra, P., Maity, S. & Mukhopadhyay, S. Liquid–liquid phase separation is driven by large-scale conformational unwinding and fluctuations of intrinsically disordered protein molecules. J. Phys. Chem. Lett. 10, 3929–3936 (2019).
Marrone, L. et al. FUS pathology in ALS is linked to alterations in multiple ALS-associated proteins and rescued by drugs stimulating autophagy. Acta Neuropathol. 138, 67–84 (2019).
Rai, A. K., Chen, J.-X., Selbach, M. & Pelkmans, L. Kinase-controlled phase transition of membraneless organelles in mitosis. Nature 559, 211–216 (2018).
Tauber, D. et al. Modulation of RNA condensation by the DEAD-Box protein eIF4A. Cell 180, 411–426.e16 (2020).
Hondele, M. et al. DEAD-box ATPases are global regulators of phase-separated organelles. Nature 573, 144–148 (2019).
Mugler, C. F. et al. ATPase activity of the DEAD-box protein Dhh1 controls processing body formation. eLife 5, e18746 (2016).
Jain, S. et al. ATPase-modulated stress granules contain a diverse proteome and substructure. Cell 164, 487–498 (2016).
Kroschwald, S. et al. Promiscuous interactions and protein disaggregases determine the material state of stress-inducible RNP granules. eLife 4, e06807 (2015).
Guo, L. et al. Nuclear-import receptors reverse aberrant phase transitions of RNA-binding proteins with prion-like domains. Cell 173, 677–692.e20 (2018). Guo et al. find that nuclear import receptors can reverse aberrant phase transitions of RNA-binding proteins such as FUS.
Yoshizawa, T. et al. Nuclear import receptor inhibits phase separation of FUS through binding to multiple sites. Cell 173, 693–705.e22 (2018).
Boeynaems, S. et al. Phase separation of C9orf72 dipeptide repeats perturbs stress granule dynamics. Mol. Cell 65, 1044–1055.e5 (2017).
Mateju, D. et al. An aberrant phase transition of stress granules triggered by misfolded protein and prevented by chaperone function. EMBO J. 36, 1669–1687 (2017).
White, M. R. et al. C9orf72 poly(PR) dipeptide repeats disturb biomolecular phase separation and disrupt nucleolar function. Mol. Cell 74, 713–728.e6 (2019).
Lee, K.-H. et al. C9orf72 dipeptide repeats impair the assembly, dynamics, and function of membrane-less organelles. Cell 167, 774–788.e17 (2016). Lee et al. show that DRPs accumulate in various condensates and affect condensate properties, assembly and disassembly.
Weber, C., Michaels, T. & Mahadevan, L. Spatial control of irreversible protein aggregation. eLife 8, e42315 (2019).
Choi, S. I. et al. Protein solubility and folding enhancement by interaction with RNA. PLoS ONE 3, e2677 (2008).
Apicco, D. J. et al. Reducing the RNA binding protein TIA1 protects against tau-mediated neurodegeneration in vivo. Nat. Neurosci. 21, 72–80 (2018).
Ganassi, M. et al. A surveillance function of the HSPB8-BAG3-HSP70 chaperone complex ensures stress granule integrity and dynamism. Mol. Cell 63, 796–810 (2016).
Bounedjah, O. et al. Free mRNA in excess upon polysome dissociation is a scaffold for protein multimerization to form stress granules. Nucleic Acids Res. 42, 8678–8691 (2014).
Schubert, U. et al. Rapid degradation of a large fraction of newly synthesized proteins by proteasomes. Nature 404, 770–774 (2000).
Brandman, O. & Hegde, R. S. Ribosome-associated protein quality control. Nat. Struct. Mol. Biol. 23, 7–15 (2016).
Kapur, M. & Ackerman, S. L. mRNA translation gone awry: translation fidelity and neurological disease. Trends Genet. 34, 218–231 (2018).
Mediani, L. et al. Defective ribosomal products challenge nuclear function by impairing nuclear condensate dynamics and immobilizing ubiquitin. EMBO J. 38, e101341 (2019). Mediani et al. report that DRiPs accumulate in the nucleolus and PML bodies, changing their physical properties.
Pohl, C. & Dikic, I. Cellular quality control by the ubiquitin-proteasome system and autophagy. Science 366, 818–822 (2019).
Kwon, S., Zhang, Y. & Matthias, P. The deacetylase HDAC6 is a novel critical component of stress granules involved in the stress response. Genes Dev. 21, 3381–3394 (2007).
Xie, X. et al. Deubiquitylases USP5 and USP13 are recruited to and regulate heat-induced stress granules through their deubiquitylating activities. J. Cell Sci. 131, jcs210856 (2018).
Dao, T. P. et al. Ubiquitin modulates liquid-liquid phase separation of UBQLN2 via disruption of multivalent interactions. Mol. Cell 69, 965–978.e6 (2018).
Turakhiya, A. et al. ZFAND1 recruits p97 and the 26S proteasome to promote the clearance of arsenite-induced stress granules. Mol. Cell 70, 906–919.e7 (2018).
Buchan, J. R., Kolaitis, R.-M., Taylor, J. P. & Parker, R. Eukaryotic stress granules are cleared by autophagy and Cdc48/VCP function. Cell 153, 1461–1474 (2013).
Sun, D., Wu, R., Zheng, J., Li, P. & Yu, L. Polyubiquitin chain-induced p62 phase separation drives autophagic cargo segregation. Cell Res. 28, 405–415 (2018).
Fujioka, Y. et al. Phase separation organizes the site of autophagosome formation. Nature 578, 301–305 (2020).
Wang, Z. & Zhang, H. Phase separation, transition, and autophagic degradation of proteins in development and pathogenesis. Trends Cell Biol. 29, 417–427 (2019).
Zhang, Y. et al. SEPA-1 mediates the specific recognition and degradation of P granule components by autophagy in C. elegans. Cell 136, 308–321 (2009).
Min, H., Lee, Y.-U., Shim, Y.-H. & Kawasaki, I. Autophagy of germ-granule components, PGL-1 and PGL-3, contributes to DNA damage-induced germ cell apoptosis in C. elegans. PLoS Genet. 15, e1008150 (2019).
Zhang, G., Wang, Z., Du, Z. & Zhang, H. mTOR regulates phase separation of PGL granules to modulate their autophagic degradation. Cell 174, 1492–1506.e22 (2018).
Hernebring, M., Brolén, G., Aguilaniu, H., Semb, H. & Nyström, T. Elimination of damaged proteins during differentiation of embryonic stem cells. Proc. Natl Acad. Sci. USA 103, 7700–7705 (2006).
Bufalino, M. R., DeVeale, B. & van der Kooy, D. The asymmetric segregation of damaged proteins is stem cell-type dependent. J. Cell Biol. 201, 523–530 (2013).
Rujano, M. A. et al. Polarised asymmetric inheritance of accumulated protein damage in higher eukaryotes. PLoS Biol. 4, e417 (2006).
Moore, D., Pilz, G., Araúzo-Bravo, M., Barral, Y. & Jessberger, S. A mechanism for the segregation of age in mammalian neural stem cells. Science 349, 1334–1338 (2015).
Kaganovich, D., Kopito, R. & Frydman, J. Misfolded proteins partition between two distinct quality control compartments. Nature 454, 1088–1095 (2008).
Sontag, E. M., Samant, R. S. & Frydman, J. Mechanisms and functions of spatial protein quality control. Annu. Rev. Biochem. 86, 97–122 (2017).
Miller, S. B. M. et al. Compartment-specific aggregases direct distinct nuclear and cytoplasmic aggregate deposition. EMBO J. 34, 778–797 (2015).
Specht, S., Miller, S. B. M., Mogk, A. & Bukau, B. Hsp42 is required for sequestration of protein aggregates into deposition sites in Saccharomyces cerevisiae. J. Cell Biol. 195, 617–629 (2011).
Spokoini, R. et al. Confinement to organelle-associated inclusion structures mediates asymmetric inheritance of aggregated protein in budding yeast. Cell Rep. 2, 738–747 (2012).
Escusa-Toret, S., Vonk, W. I. M. & Frydman, J. Spatial sequestration of misfolded proteins by a dynamic chaperone pathway enhances cellular fitness during stress. Nat. Cell Biol. 15, 1231–1243 (2013).
Frottin, F. et al. The nucleolus functions as a phase-separated protein quality control compartment. Science 365, 342–347 (2019). The study by Frottin et al. shows that the nucleolus functions as a protein quality compartment for nuclear misfolded proteins.
Audas, T. E. et al. Adaptation to stressors by systemic protein amyloidogenesis. Dev. Cell https://doi.org/10.1016/j.devcel.2016.09.002 (2016).
Munder, M. C. et al. A pH-driven transition of the cytoplasm from a fluid- to a solid-like state promotes entry into dormancy. eLife 5, e09347 (2016).
Webb, B. A., Chimenti, M., Jacobson, M. P. & Barber, D. L. Dysregulated pH: a perfect storm for cancer progression. Nat. Rev. Cancer 11, 671–677 (2011).
Akerfelt, M., Morimoto, R. I. & Sistonen, L. Heat shock factors: integrators of cell stress, development and lifespan. Nat. Rev. Mol. Cell Biol. 11, 545–555 (2010).
Malinovska, L., Kroschwald, S., Munder, M. C., Richter, D. & Alberti, S. Molecular chaperones and stress-inducible protein-sorting factors coordinate the spatiotemporal distribution of protein aggregates. Mol. Biol. Cell 23, 3041–3056 (2012).
Ungelenk, S. et al. Small heat shock proteins sequester misfolding proteins in near-native conformation for cellular protection and efficient refolding. Nat. Commun. 7, 13673 (2016).
Ho, C.-T. et al. Cellular sequestrases maintain basal Hsp70 capacity ensuring balanced proteostasis. Nat. Commun. 10, 4851 (2019).
Shorter, J. & Southworth, D. R. Spiraling in control: structures and mechanisms of the Hsp104 disaggregase. Cold Spring Harb. Perspect. Biol. 11, a034033 (2019).
Cherkasov, V. et al. Coordination of translational control and protein homeostasis during severe heat stress. Curr. Biol. 23, 2452–2462 (2013).
Wallace, E. W. J. et al. Reversible, specific, active aggregates of endogenous proteins assemble upon heat stress. Cell 162, 1286–1298 (2015).
López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. The hallmarks of aging. Cell 153, 1194–1217 (2013).
Labbadia, J. & Morimoto, R. I. The biology of proteostasis in aging and disease. Annu. Rev. Biochem. 84, 435–464 (2015).
Hartl, F. U. Cellular homeostasis and aging. Annu. Rev. Biochem. 85, 1–4 (2016).
Hara, T. et al. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441, 885–889 (2006).
Komatsu, M. et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441, 880–884 (2006).
McGurk, L. et al. Poly(ADP-ribose) prevents pathological phase separation of TDP-43 by promoting liquid demixing and stress granule localization. Mol. Cell 703-717.e9 (2018).
Shin, Y. et al. Spatiotemporal control of intracellular phase transitions using light-activated optodroplets. Cell 168, 159–171.e14 (2017).
Ramaswami, M., Taylor, J. P. & Parker, R. Altered ribostasis: RNA-protein granules in degenerative disorders. Cell 154, 727–736 (2013).
Zhang, P. et al. Chronic optogenetic induction of stress granules is cytotoxic and reveals the evolution of ALS-FTD pathology. eLife 8, e39578 (2019).
Mann, J. R. et al. RNA binding antagonizes neurotoxic phase transitions of TDP-43. Neuron 102, 321–338.e8 (2019).
Gasset-Rosa, F. et al. Cytoplasmic TDP-43 de-mixing independent of stress granules drives inhibition of nuclear import, loss of nuclear TDP-43, and cell death. Neuron 102, 339–357.e7 (2019).
Asakawa, K., Handa, H. & Kawakami, K. Optogenetic modulation of TDP-43 oligomerization accelerates ALS-related pathologies in the spinal motor neurons. Nat. Commun. 11, 1004 (2020).
Gopal, P. P., Nirschl, J. J., Klinman, E. & Holzbaur, E. L. F. Amyotrophic lateral sclerosis-linked mutations increase the viscosity of liquid-like TDP-43 RNP granules in neurons. Proc. Natl Acad. Sci. USA 114, E2466–E2475 (2017).
Alberti, S. & Carra, S. Quality control of membraneless organelles. J. Mol. Biol. 430, 4711–4729 (2018).
Alberti, S., Mateju, D., Mediani, L. & Carra, S. Granulostasis: protein quality control of RNP granules. Front. Mol. Neurosci. 10, 84 (2017).
Sen, P., Shah, P. P., Nativio, R. & Berger, S. L. Epigenetic mechanisms of longevity and aging. Cell 166, 822–839 (2016).
Adams, P. D. Remodeling of chromatin structure in senescent cells and its potential impact on tumor suppression and aging. Gene 397, 84–93 (2007).
Sanulli, S. et al. HP1 reshapes nucleosome core to promote phase separation of heterochromatin. Nature 575, 390–394 (2019).
Gibson, B. A. et al. Organization of chromatin by intrinsic and regulatephase D separation. Cell 179, 470–484.e21 (2019).
Larson, A. G. et al. Liquid droplet formation by HP1α suggests a role for phase separation in heterochromatin. Nature 547, 236–240 (2017).
Strom, A. R. et al. Phase separation drives heterochromatin domain formation. Nature 547, 241–245 (2017).
Stegeman, R. & Weake, V. M. Transcriptional signatures of aging. J. Mol. Biol. 429, 2427–2437 (2017).
Naumann, M. et al. Impaired DNA damage response signaling by FUS-NLS mutations leads to neurodegeneration and FUS aggregate formation. Nat. Commun. 9, 335 (2018).
Kilic, S. et al. Phase separation of 53BP1 determines liquid-like behavior of DNA repair compartments. EMBO J. 38, e101379 (2019).
Min, J., Wright, W. E. & Shay, J. W. Clustered telomeres in phase-separated nuclear condensates engage mitotic DNA synthesis through BLM and RAD52. Genes Dev. 33, 814–827 (2019).
Case, L. B., Ditlev, J. A. & Rosen, M. K. Regulation of transmembrane signaling by phase separation. Annu. Rev. Biophys. 48, 465–494 (2019).
Niaki, A. G. et al. Loss of dynamic RNA interaction and aberrant phase separation induced by two distinct types of ALS/FTD-linked FUS mutations. Mol. Cell 77, 82–94.e4 (2020).
Cloer, E. W. et al. p62-dependent phase separation of patient-derived KEAP1 mutations and NRF2. Mol. Cell. Biol. https://doi.org/10.1128/MCB.00644-17 (2018).
Morelli, F. F. et al. Aberrant compartment formation by HSPB2 mislocalizes lamin a and compromises nuclear integrity and function. Cell Rep. 20, 2100–2115 (2017).
Jain, A. & Vale, R. D. RNA phase transitions in repeat expansion disorders. Nature 546, 243–247 (2017).
Peskett, T. R. et al. A liquid to solid phase transition underlying pathological huntingtin Exon1 aggregation. Mol. Cell 70, 588–601.e6 (2018).
Bouchard, J. J. et al. Cancer mutations of the tumor suppressor SPOP disrupt the formation of active, phase-separated compartments. Mol. Cell 72, 19–36.e8 (2018).
Latonen, L. Nucleolar aggresomes as counterparts of cytoplasmic aggresomes in proteotoxic stress. Bioessays 33, 386–395 (2011).
Miller, S. B. M., Mogk, A. & Bukau, B. Spatially organized aggregation of misfolded proteins as cellular stress defense strategy. J. Mol. Biol. 427, 1564–1574 (2015).
Hegyi, H. & Tompa, P. Intrinsically disordered proteins display no preference for chaperone binding in vivo. PLoS Comput. Biol. 4, e1000017 (2008).
Mine, Y., Noutomi, T. & Haga, N. Thermally induced changes in egg white proteins. J. Agric. Food Chem. 38, 2122–2125 (1990).
Ciryam, P. et al. Spinal motor neuron protein supersaturation patterns are associated with inclusion body formation in ALS. Proc. Natl Acad. Sci. USA 114, E3935–E3943 (2017).
Ciryam, P., Kundra, R., Morimoto, R. I., Dobson, C. M. & Vendruscolo, M. Supersaturation is a major driving force for protein aggregation in neurodegenerative diseases. Trends Pharmacol. Sci. 36, 72–77 (2015).
Ciryam, P., Tartaglia, G. G., Morimoto, R. I., Dobson, C. M. & Vendruscolo, M. Widespread aggregation and neurodegenerative diseases are associated with supersaturated proteins. Cell Rep. 5, 781–790 (2013).
Chiti, F. & Dobson, C. M. Protein misfolding, functional amyloid, and human disease. Annu. Rev. Biochem. 75, 333–366 (2006).
Liebman, S. W. & Chernoff, Y. O. Prions in yeast. Genetics 191, 1041–1072 (2012).
Harvey, Z. H., Chen, Y. & Jarosz, D. F. Protein-based inheritance: epigenetics beyond the chromosome. Mol. Cell 69, 195–202 (2017).
True, H. L. & Lindquist, S. L. A yeast prion provides a mechanism for genetic variation and phenotypic diversity. Nature 407, 477–483 (2000).
Si, K. & Kandel, E. R. The role of functional prion-like proteins in the persistence of memory. Cold Spring Harb. Perspect. Biol. 8, a021774 (2016).
Cai, X., Xu, H. & Chen, Z. J. Prion-like polymerization in immunity and inflammation. Cold Spring Harb. Perspect. Biol. 9, a021774 (2017).
King, O. D., Gitler, A. D. & Shorter, J. The tip of the iceberg: RNA-binding proteins with prion-like domains in neurodegenerative disease. Brain Res. 1462, 61–80 (2012).
Malinovska, L., Kroschwald, S. & Alberti, S. Protein disorder, prion propensities, and self-organizing macromolecular collectives. Biochim. Biophys. Acta 1834, 918–931 (2013).
Han, T. W. et al. Cell-free formation of RNA granules: bound RNAs identify features and components of cellular assemblies. Cell 149, 768–779 (2012).
Kwon, I. et al. Phosphorylation-regulated binding of RNA polymerase II to fibrous polymers of low-complexity domains. Cell 155, 1049–1060 (2013).
Martin, E. W. et al. Valence and patterning of aromatic residues determine the phase behavior of prion-like domains. Science 367, 694–699 (2020).
Brady, J. P. et al. Structural and hydrodynamic properties of an intrinsically disordered region of a germ cell-specific protein on phase separation. Proc. Natl Acad. Sci. USA 114, E8194–E8203 (2017).
Ryan, V. H. et al. Mechanistic view of hnRNPA2 low-complexity domain structure, interactions, and phase separation altered by mutation and arginine methylation. Mol. Cell 69, 465–479.e7 (2018).
Acknowledgements
S.A. acknowledges funding by the European Research Council (PhaseAge, 725836) and the Deutsche Forschungsgemeinschaft (SPP 2191). We also thank our colleagues Serena Carra, Axel Mogk, Titus Franzmann, Rohit Pappu, Ivan Dikic, Christoph Weber and Jordina Guillen-Boixet for their helpful comments. A.A.H. acknowledges funding from the Max Planck Society and the NOMIS foundation.
Author information
Authors and Affiliations
Contributions
S.A. and A.A.H. contributed equally to all aspects of the writing and editing of the manuscript.
Corresponding authors
Ethics declarations
Competing interests
S.A. is an adviser and A.A.H. a founder of Dewpoint Therapeutics.
Additional information
Peer review information
Nature Reviews Molecular Cell Biology thanks Monika Fuxreiter and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Glossary
- Intrinsically disordered
-
An intrinsically disordered protein or region lacks a dominant 3D structure and adopts a range of conformational states.
- Avidity
-
Refers to the accumulated strength of multiple individual interactions between two molecules and is commonly referred to as functional affinity.
- Cooperativity
-
A key feature of systems of interacting molecular components that leads to collective properties not present in the individual components.
- Multivalence
-
Valence or valency is the number of chemical bonds that a molecule can form, with multivalence referring to a molecule with a valence greater than two.
- Head-to-tail polymerization
-
Refers to the mechanism of polymerization of biomolecules with two distinct interaction surfaces (a head and a tail) that have to interact in order to assemble into a polymer.
- Heterotypic interactions
-
Refers to interactions between dissimilar molecules, the opposite being homotypic interactions.
- Hydrotrope
-
A compound that solubilizes hydrophobic compounds in aqueous solutions by means other than micellar solubilization.
- Optical tweezers
-
A scientific instrument that uses a highly focused laser beam to hold and move microscopic objects such as droplets in a manner similar to tweezers.
- Prion-like disordered regions
-
A segment of a protein that is intrinsically disordered and similar in amino acid composition to yeast prions, which contain a large fraction of polar amino acids such as asparagine, glutamine and serine.
- Amyloid fibrils
-
Amyloids are aggregates of proteins characterized by a fibrillar morphology, a β-sheet secondary structure and the ability to be stained by particular dyes such as Congo red and thioflavin T.
- Cross-β-sheets
-
A highly ordered and tightly packed secondary structure in which individual β-strands are arranged into sheets with an orientation perpendicular to the axis of the fibre.
- hnRNPA1
-
Heterogeneous nuclear ribonucleoprotein A1 is a nuclear RNA-binding protein that has been linked to amyotrophic lateral sclerosis and multisystem proteinopathies.
- TDP43
-
TAR DNA-binding protein 43 is a nuclear RNA-binding protein that is hyper-phosphorylated, ubiquitylated and aggregated in frontotemporal dementia and in amyotrophic lateral sclerosis.
- Tau
-
A protein that has been linked to various neurodegenerative diseases with roles in maintaining the stability of microtubules in neurons of the central nervous system.
- α-Synuclein
-
A protein that has been linked to Parkinson disease that is found mainly in neurons in specialized structures called presynaptic terminals.
- Re-entrant phase transition
-
Re-entrant behaviour of a phase transition means that a continuous change of a parameter leads to phase disappearance during one transition and reappearance in another.
- Superoxide dismutase 1
-
(SOD1). A superoxide dismutase enzyme that has been implicated in apoptosis and familial forms of amyotrophic lateral sclerosis.
- Dipeptide repeat (DPR) proteins
-
DPR proteins are generated from repeat-associated non-ATG (RAN) translation of mutant C9ORF72 transcripts and have been linked to amyotrophic lateral sclerosis and frontotemporal dementia.
- P granules
-
P granules are Caenorhabditis elegans ‘germ granules’, a class of perinuclear RNA granules specific to the germ line. They were the first condensates to be identified as liquid-like.
- Stem-cell exhaustion
-
Is the age-related deficiency of stem cells, a hallmark that is directly responsible for many of the problems associated with ageing such as frailty and a weakened immune system.
Rights and permissions
About this article
Cite this article
Alberti, S., Hyman, A.A. Biomolecular condensates at the nexus of cellular stress, protein aggregation disease and ageing. Nat Rev Mol Cell Biol 22, 196–213 (2021). https://doi.org/10.1038/s41580-020-00326-6
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41580-020-00326-6
This article is cited by
-
Nuclear-import receptors as gatekeepers of pathological phase transitions in ALS/FTD
Molecular Neurodegeneration (2024)
-
Principles of organelle positioning in motile and non-motile cells
EMBO Reports (2024)
-
Protein thermal sensing regulates physiological amyloid aggregation
Nature Communications (2024)
-
Micropolarized to the core
Nature Chemical Biology (2024)
-
LATS2 condensates organize signalosomes for Hippo pathway signal transduction
Nature Chemical Biology (2024)
