The Nuclear SUMO-Targeted Ubiquitin Quality Control Network Regulates the Dynamics of Cytoplasmic Stress Granules

Keiten-Schmitz, Jan; Wagner, Kristina; Piller, Tanja; Kaulich, Manuel; Alberti, Simon; Müller, Stefan

doi:10.1016/j.molcel.2020.05.017

Cited by 87 publications

(94 citation statements)

References 74 publications

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“…In a subset of ALS or FTLD patients, mutations in FUS or TDP-43 induce a transition of SGs from a liquid-like dynamic to a solid state and FUS/TDP-43 aggregates are found in affected brain regions of patients suffering from ALS or FTLD. Interestingly, we could demonstrate that the StUbL pathway limits the formation of aberrant SGs caused by expression of the ALS-associated FUS P525L mutant, pointing to a possible role of SUMO in protecting from ALS pathology (Keiten-Schmitz et al, 2020;Marmor-Kollet et al, 2020). In support of this idea, Marmor-Kollet and colleagues provided evidence that impairment of the SUMO pathway may affect formation of aberrant SGs and ALS pathology in the context of C9orf72 mutations.…”

Section: Sumo and The Dynamics Of Stress Granulesmentioning

confidence: 71%

“…Intriguingly, stress-induced SUMOylation and the E3 SUMO ligase ZNF451 are required for NELF condensation providing another intriguing example how the SUMO system integrates the cellular stress response with phase separation. Another important aspect for future research concerns the role of SUMO conjugation-deconjugation in regulating the interdependency and interplay of distinct MLO, such as PML NBs with nucleoli and SGs, under stress (Condemine et al, 2007;Keiten-Schmitz et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

“…The mechanism of SG formation and dissolution are still not fully understood, but there is accumulating evidence that post-translational modifications contribute to these processes (Turakhiya et al, 2018;Hofweber and Dormann, 2019;Hofmann et al, 2021;Tolay and Buchberger, 2021). Recent independent findings by the Hornstein and Müller groups suggest that the SUMO system and the StUbL pathway are critically involved in both assembly and dissolution of SGs (Keiten-Schmitz et al, 2020;Marmor-Kollet et al, 2020). A role of SUMOylation in modulating the formation and composition of SGs was initially inferred from work on eIF4A2, a subunit of the capbinding eIF4 complex (Jongjitwimol et al, 2016).…”

Section: Sumo and The Dynamics Of Stress Granulesmentioning

confidence: 99%

See 2 more Smart Citations

SUMO: Glue or Solvent for Phase-Separated Ribonucleoprotein Complexes and Molecular Condensates?

Keiten-Schmitz

Röder

Hornstein

et al. 2021

Front. Mol. Biosci.

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Spatial organization of cellular processes in membranous or membrane-less organelles (MLOs, alias molecular condensates) is a key concept for compartmentalizing biochemical pathways. Prime examples of MLOs are the nucleolus, PML nuclear bodies, nuclear splicing speckles or cytosolic stress granules. They all represent distinct sub-cellular structures typically enriched in intrinsically disordered proteins and/or RNA and are formed in a process driven by liquid-liquid phase separation. Several MLOs are critically involved in proteostasis and their formation, disassembly and composition are highly sensitive to proteotoxic insults. Changes in the dynamics of MLOs are a major driver of cell dysfunction and disease. There is growing evidence that post-translational modifications are critically involved in controlling the dynamics and composition of MLOs and recent evidence supports an important role of the ubiquitin-like SUMO system in regulating both the assembly and disassembly of these structures. Here we will review our current understanding of SUMO function in MLO dynamics under both normal and pathological conditions.

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Section: Sumo and The Dynamics Of Stress Granulesmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Section: Sumo and The Dynamics Of Stress Granulesmentioning

confidence: 99%

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SUMO: Glue or Solvent for Phase-Separated Ribonucleoprotein Complexes and Molecular Condensates?

Keiten-Schmitz

Röder

Hornstein

et al. 2021

Front. Mol. Biosci.

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“…The SUMO-targeted ubiquitin ligase (StUbL) pathway could establish an interdependence relationship between SUMOylation of RBPs in the cell nucleus and dissolution of SGs in the cytosol. A failure in this system was shown to enhance the pathological aggregation of this FUS mutant (Keiten-Schmitz et al, 2020).…”

Section: Neurodegenerative Diseasesmentioning

confidence: 91%

Post-translational Control of RNA-Binding Proteins and Disease-Related Dysregulation

Velázquez‐Cruz

Baños-Jaime

Díaz‐Quintana

et al. 2021

Front. Mol. Biosci.

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Cell signaling mechanisms modulate gene expression in response to internal and external stimuli. Cellular adaptation requires a precise and coordinated regulation of the transcription and translation processes. The post-transcriptional control of mRNA metabolism is mediated by the so-called RNA-binding proteins (RBPs), which assemble with specific transcripts forming messenger ribonucleoprotein particles of highly dynamic composition. RBPs constitute a class of trans-acting regulatory proteins with affinity for certain consensus elements present in mRNA molecules. However, these regulators are subjected to post-translational modifications (PTMs) that constantly adjust their activity to maintain cell homeostasis. PTMs can dramatically change the subcellular localization, the binding affinity for RNA and protein partners, and the turnover rate of RBPs. Moreover, the ability of many RBPs to undergo phase transition and/or their recruitment to previously formed membrane-less organelles, such as stress granules, is also regulated by specific PTMs. Interestingly, the dysregulation of PTMs in RBPs has been associated with the pathophysiology of many different diseases. Abnormal PTM patterns can lead to the distortion of the physiological role of RBPs due to mislocalization, loss or gain of function, and/or accelerated or disrupted degradation. This Mini Review offers a broad overview of the post-translational regulation of selected RBPs and the involvement of their dysregulation in neurodegenerative disorders, cancer and other pathologies.

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“…Very recently, the small ubiquitin-like modifier (SUMO) system and the SUMO-targeted Ub E3 ligase RNF4 were implicated in the process of SG clearance (Keiten-Schmitz et al, 2020;Marmor-Kollet et al, 2020). Therefore, we tested the possibility that the SGassociated Ub conjugates represent, at least in part, mixed SUMO-Ub chains.…”

Section: Sg Association Of Ubiquitin Chains Is Independent Of the Summentioning

confidence: 99%

Comparative profiling of stress granule clearance reveals differential contributions of the ubiquitin system

Tolay

Buchberger

2021

Life Sci. Alliance

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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.

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The Nuclear SUMO-Targeted Ubiquitin Quality Control Network Regulates the Dynamics of Cytoplasmic Stress Granules

Cited by 87 publications

References 74 publications

SUMO: Glue or Solvent for Phase-Separated Ribonucleoprotein Complexes and Molecular Condensates?

SUMO: Glue or Solvent for Phase-Separated Ribonucleoprotein Complexes and Molecular Condensates?

Post-translational Control of RNA-Binding Proteins and Disease-Related Dysregulation

Comparative profiling of stress granule clearance reveals differential contributions of the ubiquitin system

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