Spatio-Temporal Proteomic Analysis of Stress Granule Disassembly Using APEX Reveals Regulation by SUMOylation and Links to ALS Pathogenesis

Kollet, Hagai Marmor; Siany, Aviad; Kedersha, Nancy; Knafo, Naama; Rivkin, Natalia; Danino, Yehuda M.; Olender, Tsviya; Cohen, Nir; Moens, Thomas; Higginbottom, Adrian; Cooper‐Knock, Johnathan; Eitan, Chen; Cohen, Beata Toth; Bosch, Ludo Van Den; Anderson, Paul; Иванов, П. А.; Geiger, Tamar; Hornstein, Eran

doi:10.2139/ssrn.3537940

Cited by 5 publications

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“…SUMOylation's role in affecting the stability of hnRNPs and localization of actin components to the nucleus has previously been reported (Hofmann et al, 2009;Lee et al, 2012). Finally, a recent study showed that SUMOylation of stress granule proteins is required for disassembly, which is impaired by C9ORF72-associated dipeptide repeats (Marmor-Kollet et al, 2020). Our analysis suggests that SUMOylation may have substantial influence on transcriptional regulation in C9-ALS motor neurons.…”

Section: Ll Open Accesssupporting

confidence: 71%

An integrated multi-omic analysis of iPSC-derived motor neurons from C9ORF72 ALS patients

Lim

Kaye

et al. 2021

iScience

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Section: Ll Open Accesssupporting

confidence: 71%

An integrated multi-omic analysis of iPSC-derived motor neurons from C9ORF72 ALS patients

Lim

Kaye

et al. 2021

iScience

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“…Considering the reported number of SG cores per SG volume [13] and assuming the cores are spherical, it can be estimated that G3BP1 cores occupy approximately 2% of SG volume, although they can contain a large fraction of the RNA and proteins in SGs. As an alternative approach to analyze SG composition, methods based on proximity-dependent labeling have been used for the identification of SG-localized proteins and RNAs [16,17,[20][21][22]. A possible caveat here is that any SG-enriched component that has been used as a bait, but is still present in cytosol to some extent, could lead to the detection of proteins or RNAs that interact with the bait only in the cytosol.…”

Section: Challenges In Investigating Sg Functionmentioning

confidence: 99%

Stress granules: regulators or by‐products?

Matějů

Chao

2021

The FEBS Journal

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Cells have to deal with conditions that can cause damage to biomolecules and eventually cell death. To protect against these adverse conditions and promote recovery, cells undergo dramatic changes upon exposure to stress. This involves activation of signaling pathways, cell cycle arrest, translational reprogramming, and reorganization of the cytoplasm. Notably, many stress conditions cause a global inhibition of mRNA translation accompanied by the formation of cytoplasmic condensates called stress granules (SGs), which sequester mRNA together with RNA‐binding proteins, translation initiation factors, and other components. SGs are highly conserved in eukaryotes, suggesting that they perform an important function during the stress response. Over the years, many different roles have been assigned to SGs, including translational control, mRNA storage, regulation of mRNA decay, antiviral innate immune response, and modulation of signaling pathways. Most of our understanding, however, has been deduced from correlative data based upon the composition of SGs and only recently have technological innovations allowed hypotheses for SG function to be directly tested. Here, we discuss these challenges and explore the evidence related to the function of SGs.

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“…It will be of interest to investigate in more detail of the CrPV-1A/Nup358 interactions and whether ubiquitination of Nup358 is required for degradation or inactivation. Although the mammalian Nup358 is also a small ubiquitin-like modifier (SUMO) E3 ligase, that can SUMOylate Ago2 and is linked to SG dynamics (85)(86)(87)(88)(89), however the Drosophila Nup358 lacks an obvious sumoylation domain (73).…”

Section: Further Our Results Identified Nup358 As a Key Component In ...mentioning

confidence: 99%

Targeting Nup358/RanBP2 by a viral protein disrupts stress granule formation

Sadasivan

Vlok

Wang

et al. 2022

Preprint

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Viruses have evolved mechanisms to modulate cellular pathways to facilitate infection. One such pathway is the formation of stress granules (SG), which are ribonucleoprotein complexes that assemble during translation inhibition following cellular stress. Inhibition of SG assembly has been observed under numerous virus infections across species, suggesting a conserved fundamental viral strategy. However, the significance of SG modulation during virus infection is not fully understood. The 1A protein encoded by the model dicistrovirus, Cricket Paralysis Virus (CrPV), is a multifunctional protein that can bind to and degrade Ago-2 in an E3 ubiquitin ligase-dependent manner to block the antiviral RNA interference pathway and inhibit SG formation. Moreover, the R146 residue of 1A is necessary for SG inhibition and CrPV infection in both Drosophila S2 cells and adult flies. Here, we uncoupled CrPV-1A's functions and provide insight into its underlying mechanism for SG inhibition. CrPV-1A mediated inhibition of SGs requires the E3 ubiquitin-ligase binding domain and the R146 residue, but not the Ago-2 binding domain. Wild-type but not mutant CrPV-1A R146A localizes to the nuclear membrane which correlates with nuclear enrichment of poly(A)+ RNA. Transcriptome changes in CrPV-infected cells are dependent on the R146 residue. Finally, Nup358/RanBP2 is targeted and degraded in CrPV-infected cells in an R146-dependent manner and the depletion of Nup358 blocks SG formation. We propose that CrPV utilizes a multiprong strategy whereby the CrPV-1A protein interferes with a nuclear event that contributes to SG inhibition in order to promote infection.

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Spatio-Temporal Proteomic Analysis of Stress Granule Disassembly Using APEX Reveals Regulation by SUMOylation and Links to ALS Pathogenesis

Cited by 5 publications

References 0 publications

An integrated multi-omic analysis of iPSC-derived motor neurons from C9ORF72 ALS patients

An integrated multi-omic analysis of iPSC-derived motor neurons from C9ORF72 ALS patients

Stress granules: regulators or by‐products?

Targeting Nup358/RanBP2 by a viral protein disrupts stress granule formation

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