Biomolecular condensates at the nexus of cellular stress, protein aggregation disease and ageing (original) (raw)

• 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).
  CAS PubMed PubMed Central Google Scholar
• Shin, Y. & Brangwynne, C. P. Liquid phase condensation in cell physiology and disease. Science 357, eaaf4382 (2017).
  PubMed Google Scholar
• Alberti, S., Gladfelter, A. & Mittag, T. Considerations and challenges in studying liquid-liquid phase separation and biomolecular condensates. Cell 176, 419–434 (2019).
  CAS PubMed PubMed Central Google Scholar
• Protter, D. S. W. & Parker, R. Principles and properties of stress granules. Trends Cell Biol. 26, 668–679 (2016).
  CAS PubMed PubMed Central Google Scholar
• Panas, M. D., Ivanov, P. & Anderson, P. Mechanistic insights into mammalian stress granule dynamics. J. Cell Biol. 215, 313–323 (2016).
  CAS PubMed PubMed Central Google Scholar
• Alberti, S. & Dormann, D. Liquid–liquid phase separation in disease. Annu. Rev. Genet. 53, 171–194 (2019).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• 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).
  CAS PubMed Google Scholar
• Hyman, A. A., Weber, C. A. & Jülicher, F. Liquid-liquid phase separation in biology. Annu. Rev. Cell Dev. Biol. 30, 39–58 (2014).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• Franzmann, T. M. et al. Phase separation of a yeast prion protein promotes cellular fitness. Science 359, eaao5654 (2018).
  PubMed Google Scholar
• Klosin, A. et al. Phase separation provides a mechanism to reduce noise in cells. Science 367, 464–468 (2020).
  CAS PubMed Google Scholar
• Riback, J. A. et al. Stress-triggered phase separation is an adaptive, evolutionarily tuned response. Cell 168, 1028–1040.e19 (2017).
  CAS PubMed PubMed Central Google Scholar
• Shin, Y. et al. Liquid nuclear condensates mechanically sense and restructure the genome. Cell 175, 1481–1491.e13 (2018).
  CAS PubMed PubMed Central Google Scholar
• Bienz, M. Head-to-tail polymerization in the assembly of biomolecular condensates. Cell 182, 799–811 (2020).
  CAS PubMed Google Scholar
• Wu, H. & Fuxreiter, M. The Structure and dynamics of higher-order assemblies: amyloids, signalosomes, and granules. Cell 165, 1055–1066 (2016).
  CAS PubMed PubMed Central Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• Holehouse, A. S. & Pappu, R. V. Functional implications of intracellular phase transitions. Biochemistry https://doi.org/10.1021/acs.biochem.7b01136 (2018).
  Article PubMed Google Scholar
• 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).
  Article PubMed PubMed Central Google Scholar
• 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.
  CAS PubMed PubMed Central Google Scholar
• 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.
  CAS PubMed Google Scholar
• Alberti, S. & Hyman, A. A. Are aberrant phase transitions a driver of cellular aging? Bioessays 38, 959–968 (2016).
  CAS PubMed PubMed Central Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• Li, P. et al. Phase transitions in the assembly of multivalent signalling proteins. Nature 483, 336–340 (2012).
  CAS PubMed PubMed Central Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• Nott, T. J. et al. Phase transition of a disordered nuage protein generates environmentally responsive membraneless organelles. Mol. Cell 57, 936–947 (2015).
  CAS PubMed PubMed Central Google Scholar
• 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.
  CAS PubMed PubMed Central Google Scholar
• 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).
  CAS PubMed Google Scholar
• Semenov, A. N. & Rubinstein, M. Thermoreversible gelation in solutions of associative polymers. 1. Statics. Macromolecules 31, 1373–1385 (1998).
  CAS Google Scholar
• 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).
  Article PubMed PubMed Central Google Scholar
• Riback, J. A. et al. Composition-dependent thermodynamics of intracellular phase separation. Nature 581, 209–214 (2020).
  CAS PubMed PubMed Central Google Scholar
• Banani, S. F. et al. Compositional control of phase-separated cellular bodies. Cell 166, 651–663 (2016).
  CAS PubMed PubMed Central Google Scholar
• Langeberg, L. K. & Scott, J. D. Signalling scaffolds and local organization of cellular behaviour. Nat. Rev. Mol. Cell Biol. 16, 232–244 (2015).
  CAS PubMed PubMed Central Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• 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).
  PubMed PubMed Central Google Scholar
• Yang, P. et al. G3BP1 is a tunable switch that triggers phase separation to assemble stress granules. Cell 181, 325–345.e28 (2020).
  CAS PubMed PubMed Central Google Scholar
• Sanders, D. W. et al. Competing protein-RNA interaction networks control multiphase intracellular organization. Cell 181, 306–324.e28 (2020).
  CAS PubMed PubMed Central Google Scholar
• Falahati, H. & Wieschaus, E. Independent active and thermodynamic processes govern the nucleolus assembly in vivo. Proc. Natl Acad. Sci. USA 114, 1335–1340 (2017).
  CAS PubMed PubMed Central Google Scholar
• Su, X. et al. Phase separation of signaling molecules promotes T cell receptor signal transduction. Science 352, 595–599 (2016).
  CAS PubMed PubMed Central Google Scholar
• Monahan, Z. et al. Phosphorylation of the FUS low-complexity domain disrupts phase separation, aggregation, and toxicity. EMBO J. 36, 2951–2967 (2017).
  CAS PubMed PubMed Central Google Scholar
• 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.
  CAS PubMed Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• Pavitt, G. D. eIF2B, a mediator of general and gene-specific translational control. Biochem. Soc. Trans. 33, 1487–1492 (2005).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• 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.
  CAS PubMed PubMed Central Google Scholar
• Patel, A. et al. ATP as a biological hydrotrope. Science 356, 753–756 (2017).
  CAS PubMed Google Scholar
• 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).
  PubMed PubMed Central Google Scholar
• 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).
  PubMed PubMed Central Google Scholar
• Iserman, C. et al. Condensation of Ded1p promotes a translational switch from housekeeping to stress protein production. Cell 181, 818–831.e19 (2020).
  CAS PubMed PubMed Central Google Scholar
• Jawerth, L. et al. Protein condensates as aging maxwell fluids. Science 370, 1317–1323 (2020).
  CAS PubMed Google Scholar
• Roberts, S., Dzuricky, M. & Chilkoti, A. Elastin-like polypeptides as models of intrinsically disordered proteins. FEBS Lett. 589 (19 Pt A), 2477–2486 (2015).
  CAS PubMed PubMed Central Google Scholar
• Parry, B. R. et al. The bacterial cytoplasm has glass-like properties and is fluidized by metabolic activity. Cell 156, 183–194 (2014).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• 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).
  CAS PubMed Google Scholar
• Piazza, R. Protein interactions and association: an open challenge for colloid science. Curr. Opin. Colloid Interface Sci. 8, 515–522 (2004).
  CAS Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• Serio, T. R. et al. Nucleated conformational conversion and the replication of conformational information by a prion determinant. Science 289, 1317–1321 (2000).
  CAS PubMed Google Scholar
• Chatani, E. & Yamamoto, N. Recent progress on understanding the mechanisms of amyloid nucleation. Biophys. Rev. 10, 527–534 (2018).
  CAS PubMed Google Scholar
• Jarosz, D. F. & Khurana, V. Specification of physiologic and disease states by distinct proteins and protein conformations. Cell 171, 1001–1014 (2017).
  CAS PubMed Google Scholar
• Hughes, M. P. et al. Atomic structures of low-complexity protein segments reveal kinked β sheets that assemble networks. Science 359, 698–701 (2018).
  CAS PubMed PubMed Central Google Scholar
• 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.
  CAS PubMed PubMed Central Google Scholar
• 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).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• Peran, I. & Mittag, T. Molecular structure in biomolecular condensates. Curr. Opin. Struct. Biol. 60, 17–26 (2019).
  PubMed PubMed Central Google Scholar
• Kato, M. & McKnight, S. L. Cross-β polymerization of low complexity sequence domains. Cold Spring Harb. Perspect. Biol. 9, a023598 (2017).
  PubMed PubMed Central Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• Breydo, L. & Uversky, V. N. Structural, morphological, and functional diversity of amyloid oligomers. FEBS Lett. 589, 2640–2648 (2015).
  CAS PubMed Google Scholar
• Bemporad, F. & Chiti, F. Protein misfolded oligomers: experimental approaches, mechanism of formation, and structure-toxicity relationships. Chem. Biol. 19, 315–327 (2012).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• 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.
  CAS PubMed Google Scholar
• Wegmann, S. et al. Tau protein liquid–liquid phase separation can initiate tau aggregation. EMBO J. 37, e98049 (2018).
  PubMed PubMed Central Google Scholar
• 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.
  PubMed PubMed Central Google Scholar
• Franzmann, T. M. & Alberti, S. Protein phase separation as a stress survival strategy. Cold Spring Harb. Perspect. Biol. 11, a034058 (2019).
  CAS PubMed PubMed Central Google Scholar
• Kroschwald, S. et al. Different material states of Pub1 condensates define distinct modes of stress adaptation and recovery. Cell Rep. 23, 3327–3339 (2018).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• Rai, A. K., Chen, J.-X., Selbach, M. & Pelkmans, L. Kinase-controlled phase transition of membraneless organelles in mitosis. Nature 559, 211–216 (2018).
  CAS PubMed Google Scholar
• Tauber, D. et al. Modulation of RNA condensation by the DEAD-Box protein eIF4A. Cell 180, 411–426.e16 (2020).
  CAS PubMed PubMed Central Google Scholar
• Hondele, M. et al. DEAD-box ATPases are global regulators of phase-separated organelles. Nature 573, 144–148 (2019).
  CAS PubMed Google Scholar
• Mugler, C. F. et al. ATPase activity of the DEAD-box protein Dhh1 controls processing body formation. eLife 5, e18746 (2016).
  PubMed PubMed Central Google Scholar
• Jain, S. et al. ATPase-modulated stress granules contain a diverse proteome and substructure. Cell 164, 487–498 (2016).
  CAS PubMed PubMed Central Google Scholar
• Kroschwald, S. et al. Promiscuous interactions and protein disaggregases determine the material state of stress-inducible RNP granules. eLife 4, e06807 (2015).
  PubMed PubMed Central Google Scholar
• 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.
  CAS PubMed PubMed Central Google Scholar
• Yoshizawa, T. et al. Nuclear import receptor inhibits phase separation of FUS through binding to multiple sites. Cell 173, 693–705.e22 (2018).
  CAS PubMed PubMed Central Google Scholar
• Boeynaems, S. et al. Phase separation of C9orf72 dipeptide repeats perturbs stress granule dynamics. Mol. Cell 65, 1044–1055.e5 (2017).
  CAS PubMed PubMed Central Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• 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.
  CAS PubMed PubMed Central Google Scholar
• Weber, C., Michaels, T. & Mahadevan, L. Spatial control of irreversible protein aggregation. eLife 8, e42315 (2019).
  PubMed PubMed Central Google Scholar
• Choi, S. I. et al. Protein solubility and folding enhancement by interaction with RNA. PLoS ONE 3, e2677 (2008).
  PubMed PubMed Central Google Scholar
• Apicco, D. J. et al. Reducing the RNA binding protein TIA1 protects against tau-mediated neurodegeneration in vivo. Nat. Neurosci. 21, 72–80 (2018).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• Schubert, U. et al. Rapid degradation of a large fraction of newly synthesized proteins by proteasomes. Nature 404, 770–774 (2000).
  CAS PubMed Google Scholar
• Brandman, O. & Hegde, R. S. Ribosome-associated protein quality control. Nat. Struct. Mol. Biol. 23, 7–15 (2016).
  CAS PubMed PubMed Central Google Scholar
• Kapur, M. & Ackerman, S. L. mRNA translation gone awry: translation fidelity and neurological disease. Trends Genet. 34, 218–231 (2018).
  CAS PubMed PubMed Central Google Scholar
• 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.
  PubMed PubMed Central Google Scholar
• Pohl, C. & Dikic, I. Cellular quality control by the ubiquitin-proteasome system and autophagy. Science 366, 818–822 (2019).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• 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).
  PubMed Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• 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).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• Fujioka, Y. et al. Phase separation organizes the site of autophagosome formation. Nature 578, 301–305 (2020).
  CAS PubMed Google Scholar
• Wang, Z. & Zhang, H. Phase separation, transition, and autophagic degradation of proteins in development and pathogenesis. Trends Cell Biol. 29, 417–427 (2019).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• 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).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• Rujano, M. A. et al. Polarised asymmetric inheritance of accumulated protein damage in higher eukaryotes. PLoS Biol. 4, e417 (2006).
  PubMed PubMed Central Google Scholar
• 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).
  CAS Google Scholar
• Kaganovich, D., Kopito, R. & Frydman, J. Misfolded proteins partition between two distinct quality control compartments. Nature 454, 1088–1095 (2008).
  CAS PubMed PubMed Central Google Scholar
• Sontag, E. M., Samant, R. S. & Frydman, J. Mechanisms and functions of spatial protein quality control. Annu. Rev. Biochem. 86, 97–122 (2017).
  CAS PubMed Google Scholar
• Miller, S. B. M. et al. Compartment-specific aggregases direct distinct nuclear and cytoplasmic aggregate deposition. EMBO J. 34, 778–797 (2015).
  CAS PubMed PubMed Central Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• 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).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• 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.
  CAS PubMed Google Scholar
• 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).
  Article PubMed PubMed Central Google Scholar
• 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).
  PubMed PubMed Central Google Scholar
• 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).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• 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).
  PubMed PubMed Central Google Scholar
• Ho, C.-T. et al. Cellular sequestrases maintain basal Hsp70 capacity ensuring balanced proteostasis. Nat. Commun. 10, 4851 (2019).
  PubMed PubMed Central Google Scholar
• Shorter, J. & Southworth, D. R. Spiraling in control: structures and mechanisms of the Hsp104 disaggregase. Cold Spring Harb. Perspect. Biol. 11, a034033 (2019).
  CAS PubMed PubMed Central Google Scholar
• Cherkasov, V. et al. Coordination of translational control and protein homeostasis during severe heat stress. Curr. Biol. 23, 2452–2462 (2013).
  CAS PubMed Google Scholar
• Wallace, E. W. J. et al. Reversible, specific, active aggregates of endogenous proteins assemble upon heat stress. Cell 162, 1286–1298 (2015).
  CAS PubMed PubMed Central Google Scholar
• López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. The hallmarks of aging. Cell 153, 1194–1217 (2013).
  PubMed PubMed Central Google Scholar
• Labbadia, J. & Morimoto, R. I. The biology of proteostasis in aging and disease. Annu. Rev. Biochem. 84, 435–464 (2015).
  CAS PubMed PubMed Central Google Scholar
• Hartl, F. U. Cellular homeostasis and aging. Annu. Rev. Biochem. 85, 1–4 (2016).
  CAS PubMed Google Scholar
• Hara, T. et al. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441, 885–889 (2006).
  CAS PubMed Google Scholar
• Komatsu, M. et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441, 880–884 (2006).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• Ramaswami, M., Taylor, J. P. & Parker, R. Altered ribostasis: RNA-protein granules in degenerative disorders. Cell 154, 727–736 (2013).
  CAS PubMed Google Scholar
• Zhang, P. et al. Chronic optogenetic induction of stress granules is cytotoxic and reveals the evolution of ALS-FTD pathology. eLife 8, e39578 (2019).
  PubMed PubMed Central Google Scholar
• Mann, J. R. et al. RNA binding antagonizes neurotoxic phase transitions of TDP-43. Neuron 102, 321–338.e8 (2019).
  CAS PubMed PubMed Central Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• Alberti, S. & Carra, S. Quality control of membraneless organelles. J. Mol. Biol. 430, 4711–4729 (2018).
  CAS PubMed Google Scholar
• Alberti, S., Mateju, D., Mediani, L. & Carra, S. Granulostasis: protein quality control of RNP granules. Front. Mol. Neurosci. 10, 84 (2017).
  PubMed PubMed Central Google Scholar
• Sen, P., Shah, P. P., Nativio, R. & Berger, S. L. Epigenetic mechanisms of longevity and aging. Cell 166, 822–839 (2016).
  CAS PubMed PubMed Central Google Scholar
• Adams, P. D. Remodeling of chromatin structure in senescent cells and its potential impact on tumor suppression and aging. Gene 397, 84–93 (2007).
  CAS PubMed PubMed Central Google Scholar
• Sanulli, S. et al. HP1 reshapes nucleosome core to promote phase separation of heterochromatin. Nature 575, 390–394 (2019).
  CAS PubMed PubMed Central Google Scholar
• Gibson, B. A. et al. Organization of chromatin by intrinsic and regulatephase D separation. Cell 179, 470–484.e21 (2019).
  CAS PubMed PubMed Central Google Scholar
• Larson, A. G. et al. Liquid droplet formation by HP1α suggests a role for phase separation in heterochromatin. Nature 547, 236–240 (2017).
  CAS PubMed PubMed Central Google Scholar
• Strom, A. R. et al. Phase separation drives heterochromatin domain formation. Nature 547, 241–245 (2017).
  CAS PubMed PubMed Central Google Scholar
• Stegeman, R. & Weake, V. M. Transcriptional signatures of aging. J. Mol. Biol. 429, 2427–2437 (2017).
  CAS PubMed PubMed Central Google Scholar
• 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).
  PubMed PubMed Central Google Scholar
• Kilic, S. et al. Phase separation of 53BP1 determines liquid-like behavior of DNA repair compartments. EMBO J. 38, e101379 (2019).
  PubMed PubMed Central Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• Case, L. B., Ditlev, J. A. & Rosen, M. K. Regulation of transmembrane signaling by phase separation. Annu. Rev. Biophys. 48, 465–494 (2019).
  CAS PubMed PubMed Central Google Scholar
• 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).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• Jain, A. & Vale, R. D. RNA phase transitions in repeat expansion disorders. Nature 546, 243–247 (2017).
  CAS PubMed PubMed Central Google Scholar
• Peskett, T. R. et al. A liquid to solid phase transition underlying pathological huntingtin Exon1 aggregation. Mol. Cell 70, 588–601.e6 (2018).
  CAS PubMed PubMed Central Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• Latonen, L. Nucleolar aggresomes as counterparts of cytoplasmic aggresomes in proteotoxic stress. Bioessays 33, 386–395 (2011).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• Hegyi, H. & Tompa, P. Intrinsically disordered proteins display no preference for chaperone binding in vivo. PLoS Comput. Biol. 4, e1000017 (2008).
  PubMed PubMed Central Google Scholar
• Mine, Y., Noutomi, T. & Haga, N. Thermally induced changes in egg white proteins. J. Agric. Food Chem. 38, 2122–2125 (1990).
  CAS Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• 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).
  CAS PubMed Google Scholar
• Chiti, F. & Dobson, C. M. Protein misfolding, functional amyloid, and human disease. Annu. Rev. Biochem. 75, 333–366 (2006).
  CAS PubMed Google Scholar
• Liebman, S. W. & Chernoff, Y. O. Prions in yeast. Genetics 191, 1041–1072 (2012).
  CAS PubMed PubMed Central Google Scholar
• Harvey, Z. H., Chen, Y. & Jarosz, D. F. Protein-based inheritance: epigenetics beyond the chromosome. Mol. Cell 69, 195–202 (2017).
  PubMed PubMed Central Google Scholar
• True, H. L. & Lindquist, S. L. A yeast prion provides a mechanism for genetic variation and phenotypic diversity. Nature 407, 477–483 (2000).
  CAS PubMed Google Scholar
• 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).
  PubMed PubMed Central Google Scholar
• Cai, X., Xu, H. & Chen, Z. J. Prion-like polymerization in immunity and inflammation. Cold Spring Harb. Perspect. Biol. 9, a021774 (2017).
  Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• Malinovska, L., Kroschwald, S. & Alberti, S. Protein disorder, prion propensities, and self-organizing macromolecular collectives. Biochim. Biophys. Acta 1834, 918–931 (2013).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• Kwon, I. et al. Phosphorylation-regulated binding of RNA polymerase II to fibrous polymers of low-complexity domains. Cell 155, 1049–1060 (2013).
  CAS PubMed PubMed Central Google Scholar
• Martin, E. W. et al. Valence and patterning of aromatic residues determine the phase behavior of prion-like domains. Science 367, 694–699 (2020).
  CAS PubMed PubMed Central Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar