The multi‐functional RNA‐binding protein G3BP1 and its potential implication in neurodegenerative disease

Sidibé, Hadjara; Dubinski, Alicia; Velde, Christine Vande

doi:10.1111/jnc.15280

Cited by 34 publications

(32 citation statements)

References 177 publications

(304 reference statements)

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“…The various roles of Caprin-1 in cancer as a cell cycle regulator and in neurodegenerative disease as potential contributor to altered RNA metabolism and also the roles of G3BP in viral infections, cancer and neurodegeneration disease highlight the importance of this pH-regulated interaction. This work thus uncovers new targets for the potential treatment of diseases characterized by dysregulation of SGs 7,56–58 .…”

Section: Discussionmentioning

confidence: 84%

Caprin-1 binding to the critical stress granule protein G3BP1 is regulated by pH

Schulte

Panas

Williams

et al. 2021

Preprint

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G3BP is the central hub within the protein-RNA interaction network of stress-induced bio-molecular condensates known as stress granules (SG). The SG-associated proteins Caprin-1 and USP10 exhibit mutually exclusive binding to the structured NTF2-domain of G3BP1, thereby regulating G3BP1-mediated condensation, but with opposite effects: Caprin-1 promotes but USP10 inhibits SG formation. Herein, we present the crystal structure of G3BP1-NTF2 in complex with a Caprin-1 derived short linear motif (SLiM), which provides a molecular understanding for the mutually exclusive binding of USP10 and Caprin-1 to G3BP1. Caprin-1 but not USP10 contacts two G3BP1-NTF2 histidine residues, which was confirmed using biochemical, biophysical and cellular biological binding assays. G3BP1/Caprin-1 interactions disrupted via point mutations resulted in fewer and smaller SG condensates. In addition, biochemical binding assays demonstrated reduced binding of Caprin-1 to G3BP1 at lower pH values. Finally, ratiometric pH sensitive measurements of SGs revealed a substantial drop in pH compared to the adjacent cytosol, suggesting that reduced pH can fine-tune and regulate the G3BP1-mediated interaction network via a NTF2-mediated pH-sensitive SLiM-selection mechanism.

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Section: Discussionmentioning

confidence: 84%

Caprin-1 binding to the critical stress granule protein G3BP1 is regulated by pH

Schulte

Panas

Williams

et al. 2021

Preprint

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show abstract

“…G3BP1 is a multifunctional protein best known for its role in stress granule construction and related dynamics. Evidence suggests that G3BP1 appears necessary for neural growth and survival [ 37 ]. The creation of G3BP1/mice exhibiting late embryonic lethality emphasizes the relevance of G3BP1.…”

Section: Discussionmentioning

confidence: 99%

Nobiletin Ameliorates Cellular Damage and Stress Response and Restores Neuronal Identity Altered by Sodium Arsenate Exposure in Human iPSCs-Derived hNPCs

et al. 2022

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Environmental exposure to arsenic has been profoundly associated with chronic systemic disorders, such as neurodegeneration, in both experimental models and clinical studies. The neuronal cells of the brain and the nervous system have a limited regeneration capacity, thus making them more vulnerable to exposure to xenobiotics, leading to long-lasting disabilities. The functional and anatomical complexity of these cells hinders the complete understanding of the mechanisms of neurodegeneration and neuroprotection. The present investigations aimed to evaluate the neuroprotective efficacy of a herbal formulation of Nobiletin (NOB) against the toxic insult induced by sodium arsenate (NA) in human neural progenitor cells (hNPCs) derived from human induced pluripotent stem cells (hiPSCs). Prior to the neuroprotective experiments, biologically safe doses of both NOB and NA were ascertained using standard endpoints of cytotoxicity. Thereafter, the hNPCs were exposed to either NOB (50 μM) or NA (50 μM) and co-exposed to biologically safe concentrations of NA (50 μM) with NOB (50 μM) for a period of up to 48 h. NOB treatment restored the morphological damage (neurite damage), the levels of stress granule G3BP1 (Ras-GTPase-activating protein (SH3 domain)-binding protein) and TIA1 (T cell-restricted intracellular antigen), and the expression of neuronal markers (Tuj1, Nestin, MAP2, and PAX6) when compared to NA-exposed cells. A substantial restoration of reactive oxygen species and mitochondrial membrane potential was also witnessed in the co-exposure group (NA + NOB) in comparison to the NA-exposed group. The findings suggest that NOB possesses a significant restorative/protective potential against the NA challenge in hNPCs under experimental conditions and imply that nobiletin may impart a potential therapeutic impact if studied adequately using in vivo studies.

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“…Full-length tau with internal disorder may also pass through LLPS under pathological conditions and aggregate ( 15 ). Numerous proteins involved in the composition of SGs, such as TDP-43 ( 82 - 85 ), TIA1 ( 86 , 87 ), G3BP1/2 ( 88 , 89 ), FUS ( 90 , 91 ) and heterogeneous nuclear ribonucleoproteins (hnRNPs) ( 92 , 93 ), are related to the pathogenesis of neurodegenerative diseases ( Table I ).…”

Section: Sgs Involved In Neurodegenerative Diseasesmentioning

confidence: 99%

Pathophysiology of stress granules: An emerging link to diseases (Review)

et al. 2022

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Under unfavorable environmental conditions, eukaryotic cells may form stress granules (SGs) in the cytosol to protect against injury and promote cell survival. The initiation, mRNA and protein composition, distribution and degradation of SGs are subject to multiple intracellular post-translational modifications and signaling pathways to cope with stress damage. despite accumulated comprehensive knowledge of their composition and dynamics, the function of SGs remains poorly understood. When the stress persists, aberrant and/or persistent intracellular SGs and aggregation of SGs-related proteins may lead to various diseases. In the present article, the research progress regarding the generation, modification and function of SGs was reviewed. The regulatory effects and influencing factors of SGs in the development of tumors, cardiovascular diseases, viral infections and neurodegenerative diseases were also summarized, which may provide novel insight for preventing and treating SG-related diseases.

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The multi‐functional RNA‐binding protein G3BP1 and its potential implication in neurodegenerative disease

Cited by 34 publications

References 177 publications

Caprin-1 binding to the critical stress granule protein G3BP1 is regulated by pH

Caprin-1 binding to the critical stress granule protein G3BP1 is regulated by pH

Nobiletin Ameliorates Cellular Damage and Stress Response and Restores Neuronal Identity Altered by Sodium Arsenate Exposure in Human iPSCs-Derived hNPCs

Pathophysiology of stress granules: An emerging link to diseases (Review)

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