scholarly journals Molecularly distinct cores coexist inside stress granules

2019 ◽  
Author(s):  
Luca Cirillo ◽  
Adeline Cieren ◽  
Monica Gotta
Keyword(s):  
Reverse Genetics ◽  
Core Protein ◽  
Super Resolution ◽  
Stress Granules ◽  
Stress Granule ◽  
Eukaryotic Cells ◽  
Stress Exposure ◽  
The Core ◽  
Stable Core ◽  
Liquid Liquid Phase Separation

SummaryStress granules are membraneless organelles that form in eukaryotic cells after stress exposure. Stress granules are constituted by a stable core and a dynamic shell that establishes a liquid-liquid phase separation with the surrounding cytosol. The structure and assembly of stress granules and how different components contribute to their formation are not fully understood. Here, using super resolution and expansion microscopy, we find that the stress granule component UBAP2L and the core protein G3BP1 occupy different domains inside stress granules. Since UBAP2L displays typical properties of a core protein, our results indicate that different cores coexist inside the same granule. Consistent with a role as a core protein, UBAP2L is required for stress granule assembly in several stress conditions and reverse genetics show that it acts upstream of G3BP1. We propose a model in which UBAP2L is an essential stress granule nucleator that facilitates G3BP1 core formation and stress granule assembly and growth.

scholarly journals The UBAP2L ortholog PQN-59 contributes to stress granule assembly and development in C. elegans

2021 ◽  
Author(s):  
Simona Abbatemarco ◽  
Alexandra Bondaz ◽  
Françoise Schwager ◽  
Jing Wang ◽  
Christopher M Hammell ◽  
...  
Keyword(s):  
Stress Granules ◽  
Stress Granule ◽  
Eukaryotic Cells ◽  
Stress Exposure ◽  
Exact Role ◽  
Granule Formation ◽  
Protective Function ◽  
C Elegans ◽  
Ribonucleoprotein Complexes ◽  
Higher Sensitivity

When exposed to stressful conditions, eukaryotic cells respond by inducing the formation of cytoplasmic ribonucleoprotein complexes called stress granules. Stress granules are thought to have a protective function but their exact role is still unclear. Here we use C. elegans to study two proteins that have been shown to be important for stress granule assembly in human cells: PQN-59, the ortholog of human UBAP2L, and GTBP-1, the ortholog of the human G3BP1 and G3BP2 proteins. Both proteins fall into stress granules in the embryo and in the germline when C. elegans is exposed to stressful conditions. None of the two proteins is essential for the assembly of stress induced granules, but the granules formed in absence of PQN-59 or GTBP-1 are less numerous and dissolve faster than the ones formed in control embryos. Despite these differences, pqn-59 or gtbp-1 mutant embryos do not show a higher sensitivity to stress than control embryos. pqn-59 mutants display reduced progeny and a high percentage of embryonic lethality, phenotypes that are not dependent on stress exposure and that are not shared with gtbp-1 mutants. Our data indicate that both GTBP-1 and PQN-59 contribute to stress granule formation but that PQN-59 is, in addition, required for C. elegans development.

scholarly journals PQN-59 and GTBP-1 contribute to stress granule formation but are not essential for their assembly in C. elegans embryos

2021 ◽  
Author(s):  
Simona Abbatemarco ◽  
Alexandra Bondaz ◽  
Francoise Schwager ◽  
Jing Wang ◽  
Christopher M. Hammell ◽  
...  
Keyword(s):  
Stress Granules ◽  
Human Cells ◽  
Embryonic Lethality ◽  
Stress Granule ◽  
Eukaryotic Cells ◽  
Stress Exposure ◽  
Granule Formation ◽  
C Elegans ◽  
Ribonucleoprotein Complexes ◽  
Higher Sensitivity

When exposed to stressful conditions, eukaryotic cells respond by inducing the formation of cytoplasmic ribonucleoprotein complexes called stress granules. Here we use C. elegans to study two proteins that are important for stress granule assembly in human cells: PQN-59, the human UBAP2L ortholog, and GTBP-1, the human G3BP1/2 ortholog. Both proteins assemble into stress granules in the embryo and in the germline when C. elegans is exposed to stressful conditions. None of the two proteins is essential for the assembly of stress-induced granules, as shown by the single and combined depletions by RNAi, and neither pqn-59 nor gtbp-1 mutant embryos show higher sensitivity to stress than control embryos. We find that pqn-59 mutants display reduced progeny and a high percentage of embryonic lethality, phenotypes that are not dependent on stress exposure and that are not shared with gtbp-1 mutants. Our data indicate that, in contrast to human cells, PQN-59 and GTBP-1 are not required for stress granule formation but that PQN-59 is important for C. elegans development.

scholarly journals Small molecules for modulating protein driven liquid-liquid phase separation in treating neurodegenerative disease

2019 ◽  
Author(s):  
Richard J. Wheeler ◽  
Hyun O. Lee ◽  
Ina Poser ◽  
Arun Pal ◽  
Thom Doeleman ◽  
...  
Keyword(s):  
Phase Separation ◽  
Neurodegenerative Disease ◽  
Stress Granules ◽  
Life Time ◽  
Stress Granule ◽  
Phase Behaviour ◽  
Granule Proteins ◽  
Lateral Sclerosis ◽  
Liquid Liquid Phase Separation

AbstractAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with few avenues for treatment. Many proteins implicated in ALS associate with stress granules, which are examples of liquid-like compartments formed by phase separation. Aberrant phase transition of stress granules has been implicated in disease, suggesting that modulation of phase transitions could be a possible therapeutic route. Here, we combine cell-based and protein-based screens to show that lipoamide, and its related compound lipoic acid, reduce the propensity of stress granule proteins to aggregate in vitro. More significantly, they also prevented aggregation of proteins over the life time of Caenorhabditis elegans. Observations that they prevent dieback of ALS patient-derived (FUS mutant) motor neuron axons in culture and recover motor defects in Drosophila melanogaster expressing FUS mutants suggest plausibility as effective therapeutics. Our results suggest that altering phase behaviour of stress granule proteins in the cytoplasm could be a novel route to treat ALS.

scholarly journals Ubiquitination of G3BP1 mediates stress granule disassembly in a context-specific manner

Science ◽  
2021 ◽  
Vol 372 (6549) ◽  
pp. eabf6548
Author(s):  
Youngdae Gwon ◽  
Brian A. Maxwell ◽  
Regina-Maria Kolaitis ◽  
Peipei Zhang ◽  
Hong Joo Kim ◽  
...  
Keyword(s):  
Specific Interaction ◽  
Interaction Network ◽  
Stress Granules ◽  
Stress Granule ◽  
Eukaryotic Cells ◽  
Central Protein ◽  
Specific Manner ◽  
Cultured Human Cells ◽  
Context Specific ◽  
Lateral Sclerosis

Stress granules are dynamic, reversible condensates composed of RNA and protein that assemble in eukaryotic cells in response to a variety of stressors and are normally disassembled after stress is removed. The composition and assembly of stress granules is well understood, but little is known about the mechanisms that govern disassembly. Impaired disassembly has been implicated in some diseases including amyotrophic lateral sclerosis, frontotemporal dementia, and multisystem proteinopathy. Using cultured human cells, we found that stress granule disassembly was context-dependent: Specifically in the setting of heat shock, disassembly required ubiquitination of G3BP1, the central protein within the stress granule RNA-protein network. We found that ubiquitinated G3BP1 interacted with the endoplasmic reticulum–associated protein FAF2, which engaged the ubiquitin-dependent segregase p97/VCP (valosin-containing protein). Thus, targeting of G3BP1 weakened the stress granule–specific interaction network, resulting in granule disassembly.

scholarly journals A Single Point Mutation, Asn16→Lys, Dictates the Temperature-Sensitivity of the Reovirus tsG453 Mutant

Viruses ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 289
Author(s):  
Kathleen K. M. Glover ◽  
Danica M. Sutherland ◽  
Terence S. Dermody ◽  
Kevin M. Coombs
Keyword(s):  
Amino Acid ◽  
Temperature Sensitivity ◽  
Reverse Genetics ◽  
Core Protein ◽  
Single Point ◽  
Single Amino Acid ◽  
Single Point Mutation ◽  
Temperature Sensitive ◽  
Amino Acid Substitutions ◽  
Gene Encoding

Studies of conditionally lethal mutants can help delineate the structure-function relationships of biomolecules. Temperature-sensitive (ts) mammalian reovirus (MRV) mutants were isolated and characterized many years ago. Two of the most well-defined MRV ts mutants are tsC447, which contains mutations in the S2 gene encoding viral core protein σ2, and tsG453, which contains mutations in the S4 gene encoding major outer-capsid protein σ3. Because many MRV ts mutants, including both tsC447 and tsG453, encode multiple amino acid substitutions, the specific amino acid substitutions responsible for the ts phenotype are unknown. We used reverse genetics to recover recombinant reoviruses containing the single amino acid polymorphisms present in ts mutants tsC447 and tsG453 and assessed the recombinant viruses for temperature-sensitivity by efficiency-of-plating assays. Of the three amino acid substitutions in the tsG453 S4 gene, Asn16-Lys was solely responsible for the tsG453ts phenotype. Additionally, the mutant tsC447 Ala188-Val mutation did not induce a temperature-sensitive phenotype. This study is the first to employ reverse genetics to identify the dominant amino acid substitutions responsible for the tsC447 and tsG453 mutations and relate these substitutions to respective phenotypes. Further studies of other MRV ts mutants are warranted to define the sequence polymorphisms responsible for temperature sensitivity.

scholarly journals Liquid–liquid phase separation in human health and diseases

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Bin Wang ◽  
Lei Zhang ◽  
Tong Dai ◽  
Ziran Qin ◽  
Huasong Lu ◽  
...  
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Human Health ◽  
Essential Role ◽  
Current Knowledge ◽  
Vital Role ◽  
Liquid Phase Separation ◽  
Eukaryotic Cells ◽  
Liquid Liquid Phase Separation

AbstractEmerging evidence suggests that liquid–liquid phase separation (LLPS) represents a vital and ubiquitous phenomenon underlying the formation of membraneless organelles in eukaryotic cells (also known as biomolecular condensates or droplets). Recent studies have revealed evidences that indicate that LLPS plays a vital role in human health and diseases. In this review, we describe our current understanding of LLPS and summarize its physiological functions. We further describe the role of LLPS in the development of human diseases. Additionally, we review the recently developed methods for studying LLPS. Although LLPS research is in its infancy—but is fast-growing—it is clear that LLPS plays an essential role in the development of pathophysiological conditions. This highlights the need for an overview of the recent advances in the field to translate our current knowledge regarding LLPS into therapeutic discoveries.

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