The Role of Ubiquitin in Regulating Stress Granule Dynamics

Krause, Laura J; Herrera, María Georgina; Winklhofer, Konstanze F.

doi:10.3389/fphys.2022.910759

Cited by 16 publications

(12 citation statements)

References 214 publications

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“…RNA granules are structures which facilitate the translocation and storage of mRNAs 64 . Stress granules, whilst similar, are formed when cellular stressors such as oxidative stress are present, possibly as a mechanism to reversibly block translation initiation until the stress has been removed 65,66 . Notably, similarly to TDP-43 67 , OTUD4 was shown to be important in the correct formation of stress granules 43 .…”

Section: Discussionmentioning

confidence: 99%

“…The protein is known to have roles in modulating inflammatory signalling [91] and in the alkylation damage response [90], and has more recently been demonstrated to interact with RNA binding proteins (RBPs), including TDP-43 (which aggregates in FTLD-TDP), which are important in the functioning of neuronal RNA granules and stress granules [18]. RNA granules are structures which facilitate the translocation and storage of mRNAs [37], whilst stress granules are formed when cellular stressors such as oxidative stress are present, possibly as a mechanism to reversibly block translation initiation until the stress has been removed [16, 35]. Notably, similarly to TDP-43 [6], OTUD4 was shown to be important in the correct formation of stress granules [20].…”

Section: Discussionmentioning

confidence: 99%

“…Notably, similarly to TDP-43 [6], OTUD4 was shown to be important in the correct formation of stress granules [20]. Indeed, there is much evidence as to the importance of the ubiquitin system in the functioning of stress granules [36, 55, 77]. The hypomethylation of the 5’UTR region of OTUD4 (cg21028777), which was observed as the top hit from the FTLD EWAS meta-analysis, and the inclusion of this CpG in three modules where decreased methylation was associated with increased risk of FTLD indicates that decreased methylation of this gene might be involved in the pathogenesis of FTLD.…”

Section: Discussionmentioning

confidence: 99%

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Brain DNA methylomic analysis of frontotemporal lobar degeneration revealsOTUD4in shared dysregulated signatures across pathological subtypes

Fodder

Murthy

Rizzu

et al. 2022

Preprint

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Frontotemporal lobar degeneration (FTLD) is an umbrella term describing the neuropathology of a clinically, genetically and pathologically heterogeneous group of diseases, including frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP). Among the major FTLD pathological subgroups, FTLD with TDP-43 positive inclusions (FTLD-TDP) and FTLD with tau positive inclusions (FTLD-tau) are the most common, representing about 90% of the cases. Although alterations in DNA methylation have been consistently associated with neurodegenerative diseases, namely Alzheimer’s disease, little is known for FTLD and its heterogeneous subgroups and subtypes. The main goal of this study was to investigate DNA methylation variation in FTLD-TDP and FTLD-tau. We used frontal cortex genome-wide DNA methylation profiles from three FTLD cohorts (228 individuals), generated using the Illumina 450K or EPIC arrays. We performed epigenomewide association studies (EWAS) for each cohort followed by meta-analysis to identify shared differential methylated loci across FTLD subgroups/subtypes. Additionally, we used weighted gene correlation network analysis to identify co-methylation signatures associated with FTLD and other disease-related traits. Wherever possible, we also incorporated relevant gene/protein expression data. The EWAS meta-analysis revealed four differentially methylated loci in FTLD, some of which showed altered gene and protein expression in FTLD. Two of the meta-analysis hits,OTUD4andCEBPZ, were found to be co-methylated within signatures strongly associated with FTLD. These signatures were enriched for genes implicated in the ubiquitin system, RNA/stress granule formation and glutamatergic synaptic signalling. Altogether, our findings identified novel FTLD-associated loci, and support a role for DNA methylation as a mechanism involved in the dysregulation of biological processes relevant to FTLD, highlighting novel potential avenues for therapeutic development.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Brain DNA methylomic analysis of frontotemporal lobar degeneration revealsOTUD4in shared dysregulated signatures across pathological subtypes

Fodder

Murthy

Rizzu

et al. 2022

Preprint

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“…In addition, ubiquitination is one of the PTMs that marks proteins for degradation or regulates protein activity. Ubiquitin ligases and deubiquitinating enzymes can influence SGs dynamics by modifying the ubiquitination status of key SG proteins (43,44). The ubiquitination of some stress granule components may target them for degradation, leading to SGs disassembly.…”

Section: Introductionmentioning

confidence: 99%

Modulation of stress granule dynamics by phosphorylation and ubiquitination in plants

He,

Wang,

Kim

et al. 2024

Preprint

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The Arabidopsis tandem CCCH zinc finger 1 (TZF1) is an RNA-binding protein that plays a crucial role in plant growth and stress response. TZF1 can localize to ribonucleoprotein (RNP) granules in response to various abiotic stresses. However, very little is known about the composition, function, and assembly mechanism of plant RNP granules. In this report, we show that TZF1 contains two intrinsically disordered regions (IDRs) necessary for its localization to stress granules (SGs), a subclass of RNP granules. TZF1 recruits mitogen-activated protein kinase (MAPK) signaling components and an E3 ubiquitin ligase KEEP-ON-GOING (KEG) to SGs. TZF1 is phosphorylated by MPKs and ubiquitinated by KEG. The phosphorylation sites of TZF1 were mapped by mass spectrometry. Mutant studies revealed that phosphorylation and ubiquitination of specific residues played differential roles in enhancing or reducing TZF1 SG assembly and protein-protein interaction with mitogen-activated kinase kinase 5 (MKK5) in SGs. TZF1 is extremely unstable, and its accumulation can be enhanced by proteosome inhibitor MG132. We showed that TZF1 was ubiquitinated in vivo and in vitro by KEG and TZF1 accumulated at a much lower level in gain-of-function mutantkeg-4, compared to the WT. Ubiquitination appeared to play a positive role in TZF1 SG assembly, because either single or higher order mutations caused reduced number of SGs per cell, while enhanced the coalescence of small SGs into a large nucleus-like SG encompassing the nucleus. Together, our results demonstrate that the assembly of TZF1 SGs is distinctively regulated by ubiquitination and phosphorylation.

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“…The low-complexity domain contained in many SG-associated RBPs tends to be intrinsically disordered and serves as a driving force for lipid-lipid phase separation (LLPS) that initiates the assembly of SGs [ 1 , 2 ]. Meanwhile, the composition and concentration of RBPs, the species and abundance of RNAs, the interaction between RBPs and between RBPs and RNAs, and the post-translational modifications (PTMs) of RBPs, as well as factors in the micro-environment such as pH, ionic concentration, temperature, and metabolites can also regulate or modify the process of phase separation and SG assembly [ 1 , 3 , 4 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

Role of Proteostasis Regulation in the Turnover of Stress Granules

Qian

et al. 2022

IJMS

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RNA-binding proteins (RBPs) and RNAs can form dynamic, liquid droplet-like cytoplasmic condensates, known as stress granules (SGs), in response to a variety of cellular stresses. This process is driven by liquid–liquid phase separation, mediated by multivalent interactions between RBPs and RNAs. The formation of SGs allows a temporary suspension of certain cellular activities such as translation of unnecessary proteins. Meanwhile, non-translating mRNAs may also be sequestered and stalled. Upon stress removal, SGs are disassembled to resume the suspended biological processes and restore the normal cell functions. Prolonged stress and disease-causal mutations in SG-associated RBPs can cause the formation of aberrant SGs and/or impair SG disassembly, consequently raising the risk of pathological protein aggregation. The machinery maintaining protein homeostasis (proteostasis) includes molecular chaperones and co-chaperones, the ubiquitin-proteasome system, autophagy, and other components, and participates in the regulation of SG metabolism. Recently, proteostasis has been identified as a major regulator of SG turnover. Here, we summarize new findings on the specific functions of the proteostasis machinery in regulating SG disassembly and clearance, discuss the pathological and clinical implications of SG turnover in neurodegenerative disorders, and point to the unresolved issues that warrant future exploration.

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The Role of Ubiquitin in Regulating Stress Granule Dynamics

Cited by 16 publications

References 214 publications

Brain DNA methylomic analysis of frontotemporal lobar degeneration revealsOTUD4in shared dysregulated signatures across pathological subtypes

Brain DNA methylomic analysis of frontotemporal lobar degeneration revealsOTUD4in shared dysregulated signatures across pathological subtypes

Modulation of stress granule dynamics by phosphorylation and ubiquitination in plants

Role of Proteostasis Regulation in the Turnover of Stress Granules

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