RNA buffers the phase separation behavior of prion-like RNA-binding proteins

By Shovamayee Maharana, Jie Wang, D. Papadopoulos, Doris Richter, A. Pozniakovsky, I. Poser, M. Bickle, Sandra Rizk, Jordina Guillén-Boixet, Titus M. Franzmann and 7 more. Science, 2018

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RNA and membraneless organelles Membraneless compartments can form in cells through liquidliquid phase separation (see the Perspective by Polymenidou). But what prevents these cellular condensates from randomly fusing together? Using the RNA-binding protein (RBP) Whi3, Langdon et al. demonstrated that the secondary structure of different RNA components determines the distinct biophysical and biological properties of the two types of condensates that Whi3 forms. Several RBPs, such as FUS and TDP43, contain prion-like domains and are linked to neurodegenerative diseases. These RBPs are usually soluble in the nucleus but can form pathological aggregates in the cytoplasm. Maharana et al. showed that local RNA concentrations determine distinct phase separation behaviors in different subcellular locations. The higher RNA concentrations in the nucleus act as a buffer to prevent phase separation of RBPs; when mislocalized to the cytoplasm, lower RNA concentrations trigger aggregation. Science, this issue p. 922, p. 918; see also p. 859 High concentrations of RNA prevent pathological aggregation of RNA binding proteins in the nucleus. Prion-like RNA binding proteins (RBPs) such as TDP43 and FUS are largely soluble in the nucleus but form solid pathological aggregates when mislocalized to the cytoplasm. What keeps these proteins soluble in the nucleus and promotes aggregation in the cytoplasm is still unknown. We report here that RNA critically regulates the phase behavior of prion-like RBPs. Low RNA/protein ratios promote phase separation into liquid droplets, whereas high ratios prevent droplet formation in vitro. Reduction of nuclear RNA levels or genetic ablation of RNA binding causes excessive phase separation and the formation of cytotoxic solid-like assemblies in cells. We propose that the nucleus is a buffered system in which high RNA concentrations keep RBPs soluble. Changes in RNA levels or RNA binding abilities of RBPs cause aberrant phase transitions.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/b778e39326b694e1d1ede915ed30b51132d47780

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Citations in the corpus

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).”
The 2023 terahertz science and technology roadmap (2023, background): “Local ‘solvation hotspots’, such as the so-called liquid–liquid phase separation membraneless compartments in a cell are suspected to trigger neurotoxic protein aggregation [87] (see figure 8).”
Molecular Mechanisms of TDP-43 Misfolding and Pathology in Amyotrophic Lateral Sclerosis (2019, background): “Liquid-solid phase separation (LSPS) (Maharana et al., 2018).”
A molecular grammar governing the driving forces for phase separation of prion-like RNA binding proteins (2018, positive): “This could involve changes to the saturation concentration or the material properties of the formed condensates (Zhang et al., 2015; Maharana et al., 2018).”