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Review
. 2022 May 25:13:910759.
doi: 10.3389/fphys.2022.910759. eCollection 2022.

The Role of Ubiquitin in Regulating Stress Granule Dynamics

Laura J Krause  1   2 , Maria G Herrera  1 , Konstanze F Winklhofer  1   2
Affiliations
Review

The Role of Ubiquitin in Regulating Stress Granule Dynamics

Laura J Krause et al. Front Physiol. .

Abstract

Stress granules (SGs) are dynamic, reversible biomolecular condensates, which assemble in the cytoplasm of eukaryotic cells under various stress conditions. Formation of SGs typically occurs upon stress-induced translational arrest and polysome disassembly. The increase in cytoplasmic mRNAs triggers the formation of a protein-RNA network that undergoes liquid-liquid phase separation when a critical interaction threshold has been reached. This adaptive stress response allows a transient shutdown of several cellular processes until the stress is removed. During the recovery from stress, SGs disassemble to re-establish cellular activities. Persistent stress and disease-related mutations in SG components favor the formation of aberrant SGs that are impaired in disassembly and prone to aggregation. Recently, posttranslational modifications of SG components have been identified as major regulators of SG dynamics. Here, we summarize new insights into the role of ubiquitination in affecting SG dynamics and clearance and discuss implications for neurodegenerative diseases linked to aberrant SG formation.

Keywords: FUS; G3BP; LLPS; SUMO; TDP-43; VCP/p97; ubiquitin.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
The modification of substrate proteins by ubiquitin. (A) Enzymatic cascade of ubiquitination. E1, ubiquitin-activating enzyme; E2, ubiquitin-conjugating enzyme; E3, ubiquitin ligase. (B) Different types of ubiquitination (C) X-ray crystallographic structure of ubiquitin (PDB: 1UBQ). Lysines are highlighted in pink and the methionine at the N-terminus is shown in green. Created with BioRender.com.
FIGURE 2
FIGURE 2
Schematic representation of stress granule assembly in the cell. Cells exposed to several stress conditions respond by inhibiting translation initiation of mRNAs that are not implicated in stress responses. These mRNAs interact with specific RBPs, such as TDP-43, FUS, G3BP, and undergo LLPS when a critical threshold of interactions is reached, resulting in SG formation. Both SG assembly and disassembly are regulated by PTMs, including ubiquitination. SG disassembly is promoted by K63-linked ubiquitination of G3BP and the interaction of these ubiquitin chains with VCP. Mutations in SG components, prolonged stress, and PTM dysregulation can induce the transition of SGs into pathological aggregates. The elimination of these aggregates is regulated by ubiquitination; K48-linked ubiquitin chains are well established signals for degradation by the ubiquitin-proteasome system (UPS), whereas K63-linked ubiquitination is rather implicated in autophagosomal degradation. Created with BioRender.com.
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References

    1. Afroz T., Hock E.-M., Ernst P., Foglieni C., Jambeau M., Gilhespy L. A. B., et al. (2017). Functional and Dynamic Polymerization of the ALS-Linked Protein TDP-43 Antagonizes its Pathologic Aggregation. Nat. Commun. 8, 45. 10.1038/s41467-017-00062-0 - DOI - PMC - PubMed
    1. Akimov V., Barrio-Hernandez I., Hansen S. V. F., Hallenborg P., Pedersen A.-K., Bekker-Jensen D. B., et al. (2018). UbiSite Approach for Comprehensive Mapping of Lysine and N-Terminal Ubiquitination Sites. Nat. Struct. Mol. Biol. 25, 631–640. 10.1038/s41594-018-0084-y - DOI - PubMed
    1. Alam U., Kennedy D. (2019). Rasputin a Decade on and More Promiscuous Than Ever? A Review of G3BPs. Biochimica Biophysica Acta (BBA) - Mol. Cell. Res. 1866, 360–370. 10.1016/j.bbamcr.2018.09.001 - DOI - PMC - PubMed
    1. Alberti S., Dormann D. (2019). Liquid-Liquid Phase Separation in Disease. Annu. Rev. Genet. 53, 171–194. 10.1146/annurev-genet-112618-043527 - DOI - PubMed
    1. Alberti S., Gladfelter A., Mittag T. (2019). Considerations and Challenges in Studying Liquid-Liquid Phase Separation and Biomolecular Condensates. Cell. 176, 419–434. 10.1016/j.cell.2018.12.035 - DOI - PMC - PubMed