Abstract
Stress granules (SGs) are cytoplasmic condensates containing untranslated mRNP complexes. They are induced by various proteotoxic conditions such as heat, oxidative, and osmotic stress. SGs are believed to protect mRNPs from degradation and to enable cells to rapidly resume translation when stress conditions subside. SG dynamics are controlled by various posttranslational modifications, but the role of the ubiquitin system has remained controversial. Here, we present a comparative analysis addressing the involvement of the ubiquitin system in SG clearance. Using high-resolution immunofluorescence microscopy, we found that ubiquitin associated to varying extent with SGs induced by heat, arsenite, H2O2, sorbitol, or combined puromycin and Hsp70 inhibitor treatment. SG-associated ubiquitin species included K48- and K63-linked conjugates, whereas free ubiquitin was not significantly enriched. Inhibition of the ubiquitin activating enzyme, deubiquitylating enzymes, the 26S proteasome and p97/VCP impaired the clearance of arsenite- and heat-induced SGs, whereas SGs induced by other stress conditions were little affected. Our data underline the differential involvement of the ubiquitin system in SG clearance, a process important to prevent the formation of disease-linked aberrant SGs.
Highlights
Eukaryotic cells adapt to various environmental and biotic stresses by down-regulation of bulk translation and disassembly of polysomes
RNP dynamics can be modulated by a variety of posttranslational modifications (PTMs), including methylation, glycosylation, acetylation, phosphorylation, and SUMOylation (Hofweber & Dormann, 2019; Tauber et al, 2020; Hofmann et al, 2021)
It demonstrates that K48- and K63-linked Ub chains conjugated to substrate proteins are present at stress granules (SGs) induced by different stress conditions, and it strongly suggests that these Ub conjugates represent a major fraction of SG-associated Ub
Summary
Eukaryotic cells adapt to various environmental and biotic stresses by down-regulation of bulk translation and disassembly of polysomes. Perturbations in cellular SG homeostasis ( referred to as “granulostasis”) have been linked to several degenerative disorders, including amyotrophic lateral sclerosis, frontotemporal dementia (FTD), and multisystem proteinopathy (MSP) (Taylor et al, 2016; Alberti et al, 2017; Wolozin & Ivanov, 2019) These diseases can be caused by mutant RBPs with increased LLPS propensities, by mutational impairment of proteins promoting normal SG disassembly, or by non-AUG–driven translation of dipeptide repeat polypeptides altering SG dynamics (Taylor et al, 2016; Alberti et al, 2017). Despite significant progress in elucidating the pathogenesis underlying these ageing-related disorders, the molecular mechanisms controlling granulostasis in health and disease are still incompletely understood
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
