Stress-triggered phase separation is an adaptive, evolutionarily tuned response

By Joshua A. Riback, Christopher D Katanski, Jamie L. Kear-Scott, E. Pilipenko, A. Rojek, Tobin R. Sosnick, D. A. Drummond. Cell, 2017

828 citations recorded by the source corpus.

Summary In eukaryotic cells, diverse stresses trigger coalescence of RNA-binding proteins into stress granules. In vitro, stress-granule-associated proteins can demix to form liquids, hydrogels, and other assemblies lacking fixed stoichiometry. Observing these phenomena has generally required conditions far removed from physiological stresses. We show that poly(A)-binding protein (Pab1 in yeast), a defining marker of stress granules, phase-separates and forms hydrogels in vitro upon exposure to physiological stress conditions. Other RNA-binding proteins depend upon low-complexity regions (LCRs) or RNA for phase separation, whereas Pab1’s LCR is not required for demixing, and RNA inhibits it. Based on unique evolutionary patterns, we create LCR mutations which systematically tune its biophysical properties and Pab1 phase separation in vitro and in vivo. Mutations which impede phase separation reduce organism fitness during prolonged stress. Poly(A)-binding protein thus acts as a physiological stress sensor, exploiting phase separation to precisely mark stress onset, a broadly generalizable mechanism.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/90f510bdd3470fba1cafdf8714d49599891a4ee6

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Citations in the corpus

Physical Principles Underlying the Complex Biology of Intracellular Phase Transitions (2020, background): “(139), who quantified the effects of titrating hydrophobic residues on the driving forces for collapse and phase separation of the polyA RNA binding protein PAB1.”
Phase separation of a yeast prion protein promotes cellular fitness (2018, background): “We thank the following Services and Facilities of the Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG) for their support: We thank B. Borgonovo and R. Lemaitre (Protein Expression Purification and Characterization) for help with protein expression and purification; B. Nitzsche a”
Sequence determinants of protein phase behavior from a coarse-grained model (2017, background): “found that poly(A)-binding protein 259 Pab1 exhibits LLPS behavior in the absence of its disordered domain, but does not in 260 the absence of the folded domains [14], contrary to the notion that intrinsic disorder is 261 necessary for phase separation.”
Liquid-Liquid Phase Separation in Disease. (2019, background): “On the one hand, cells have invented mechanisms to maintain proteins in a soluble state to achieve resistance against perturbations (55, 90, 100, 132).”
Competing protein-RNA interaction networks control multiphase intracellular organization (2020, positive): “Our findings reveal that despite the common assertion that weakly self-associating IDRs are critically important for LLPS, G3BP’s IDRs are dispensable for its role in SG assembly (Figure 1), and one should be wary of equating their mere presence with physiological condensation (Riback et al., 2017).”
Intrinsically disordered regions contribute promiscuous interactions to RNP granule assembly (2017, background): “…or other RNA binding proteins to create a larger multivalent assembly (Elbaum-Garfinkle et al., 2015; Feric et al., 2016; Kaiser et al., 2008; Mitrea et al., 2016; Nott et al., 2015; Pak et al., 2016; Patel et al., 2015; Riback et al., 2017; Weber and Brangwynne, 2012; Zhang et al., 2015).”
A molecular grammar governing the driving forces for phase separation of prion-like RNA binding proteins (2018, neutral): “Furthermore, for certain condensates, the material properties can change after phase separation, and distinct material properties have been linked to distinct functions and pathologies (Franzmann et al., 2018; Kwon et al., 2013; Molliex et al., 2015; Patel et al., 2015; Riback et al., 2017; Woodruff”
Protein Phase Separation: A New Phase in Cell Biology (2018, background): “phase separation in response to heat stress, which leads to the release of its bound RNA [54].”
Molecular Mechanisms of TDP-43 Misfolding and Pathology in Amyotrophic Lateral Sclerosis (2019, background): “The phase separation behavior of the RNA binding proteins, seems closely associated with their propensity to form stress granules (Molliex et al., 2015; Protter and Parker, 2016; Riback et al., 2017).”