Phase separation by low complexity domains promotes stress granule assembly and drives pathological fibrillization

By A. Molliex, Jamshid Temirov, Jihun Lee, Maura Coughlin, A. Kanagaraj, Hong Joo Kim, Tanja Mittag, J. Paul Taylor. Cell, 2015

2,420 citations recorded by the source corpus.

SUMMARY Stress granules are membrane-less organelles composed of RNA-binding proteins (RBPs) and RNA. Functional impairment of stress granules has been implicated in amyotrophic lateral sclerosis, frontotemporal dementia and multisystem proteinopathy - diseases that are characterized by fibrillar inclusions of RBPs. Genetic evidence suggests a link between persistent stress granules and the accumulation of pathological inclusions. Here we demonstrate that the RBP hnRNPA1 undergoes liquid-liquid phase separation (LLPS) into protein-rich droplets mediated by a low complexity sequence domain (LCD). While the LCD of hnRNPA1 is sufficient to mediate LLPS, the RNA recognition motifs contribute to LLPS in the presence of RNA, giving rise to several mechanisms for regulating assembly. Importantly, while not required for LLPS, fibrillization is enhanced in protein-rich droplets. We suggest that LCD-mediated LLPS contributes to the assembly of stress granules and their liquid properties, and provides a mechanistic link between persistent stress granules and fibrillar protein pathology in disease.

Subfields: Biomaterials, Molecular Biology, Surgery

View Paper: https://www.semanticscholar.org/paper/275364daf74b1193806e0329b72fc036f13d8b3e

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Citations in the corpus

Compositional Control of Phase-Separated Cellular Bodies (2016, positive): “Moreover, we and others (Molliex et al., 2015; Patel et al., 2015; Ramaswami et al., 2013; Weber and Brangwynne, 2012) speculate that pathological states of cellular bodies may also lie on the same compositional and functional continuum.”
Protein Phase Separation: A New Phase in Cell Biology (2018, background): “Both the labile-to-stable gel [15] and liquid- to-solid [14, 16] transitions could explain the pathological conversion of SGs to aggregates in ALS [78], but their exact relation to both cellular SGs and aggregates remains undetermined.”
G3BP1 is a tunable switch that triggers phase separation to assemble stress granules (2020, positive): “1 mg/ml RNaseA (Thermo Fisher) to remove RNA (Molliex et al., 2015).”
Stress-triggered phase separation is an adaptive, evolutionarily tuned response (2017, methodology): “Pab1 hydrogels, however, are distinct from previ- 1036 Cell 168, 1028–1040, March 9, 2017 ously reported RNA-binding-protein hydrogels (Kato et al., 2012; Molliex et al., 2015) in that they form at physiological concentrations and do not require a low-complexity region.”
Liquid-Liquid Phase Separation in Disease. (2019, background): “One important finding in the last four years has been that dense protein solutions have a strong thermodynamic drive to mature into more solid-like states, such as gels (6, 108, 123).”
Competing protein-RNA interaction networks control multiphase intracellular organization (2020, positive): “These micron-sized RNA-protein droplets form in mammalian cells upon translational arrest and subsequent polysome disassembly, which releases exposed RNA into the cytoplasm (‘‘RNA influx’’) (Boeynaems et al., 2017; Kedersha et al., 1999, 2002, 2016; Kroschwald et al., 2015; Molliex et al., 2015; Whe”
Intrinsically Disordered Proteins and Their “Mysterious” (Meta)Physics (2019, background): “of the fused in sarcoma (FUS) RNA-binding protein with RNA [213]; polymerization of mutant FUS forms associated with amyotrophic lateral sclerosis [215]; RNA-dependent hydrogel formation of the LC domains of RBM3, hnRNPA1, hnRNPA2, CIRBP, and the yeast Sup35 protein [213, 216]; RNA-dependent hydroge”
Phosphorylation of the FUS low‐complexity domain disrupts phase separation, aggregation, and toxicity (2017, positive): “Recent work strongly points to the ability of these domains to form functional interactions with specific sets of proteins bearing similar low-complexity (or prion-like) domains (Kato et al , 2012; Molliex et al , 2015).”
Spatiotemporal control of intracellular phase transitions using light-activated optoDroplets (2016, positive): “For each of the cluster types assembled under weak light activation, we find a strong recovery of the fluorescence signal, with nearly complete recovery for optoFUS (84 ± 16 % recovery) and optoHNRNPA1 (84 ± 8 % recovery); optoDDX4 clusters exhibit slightly less recovery (62 ± 9 % recovery).”