Activation of Gαq sequesters specific transcripts into Ago2 particles

Jackson, Lela; Rennie, Madison; Poussaint, Alison; Scarlata, Suzanne

doi:10.1038/s41598-022-12737-w

Cited by 6 publications

(7 citation statements)

References 42 publications

(56 reference statements)

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“…In further studies, we found that the stress granules formed in PC12 cells in response to Gαq activation have a district composition and sequester only two mRNAs. 39 The underlying mechanisms that control stress granule composition are unclear and are under investigation.…”

Section: ■ Resultsmentioning

confidence: 99%

Unraveling Hidden Cell Signaling Pathways Using Biophysical Methods: Application to the Gαq/Phospholipase Cβ Signaling System

Scarlata

2024

J. Phys. Chem. B

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The success of pharmaceutical therapies relies on how well cells respond to a particular drug, but accurately predicting responses can be difficult due to the complex and numerous potential molecular interactions that are possible in cells, and the responses of individuals can be variable due to cryptic and unexpected interactions. With the advancement of proteomics and fluorescence imaging methods, it is now possible to elucidate novel secondary signaling pathways and predict unexpected responses that might otherwise be missed, allowing for the development of better therapeutics. The Gαq/PLCβ signaling pathway is activated by agents that mediate allergic responses, neurotransmission, and heart rate, as well as other functions that are critical for survival. This Review describes the factors that must be considered in delineating signaling pathways and describes the novel translational role that we have uncovered for this signaling pathway.

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Section: ■ Resultsmentioning

confidence: 99%

Unraveling Hidden Cell Signaling Pathways Using Biophysical Methods: Application to the Gαq/Phospholipase Cβ Signaling System

Scarlata

2024

J. Phys. Chem. B

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“…We followed the size and number of ALG-1, the worm equivalent of Ago2, with single and repeated Gαq stimulation whose trends were similar, but smaller than those seen with G3BP1 consistent the idea that ALG-1 stress granules are a subset of G3BP1 stress granules (18). In cultured cells, Gαq activation promotes the formation of Ago2 stress granules that protect and sequester two RNAs, Chgb and ATP5f1b (see (26)). We tested whether this is the case in C.elegans neurons.…”

Section: Discussionmentioning

confidence: 99%

“…While G3BP1 is the de facto stress granule marker, Ago2 is a binding partner of PLCβ and is released as PLCβ binds to Gαq upon stimulation (18, 26). We followed the size and number of ALG-1, the worm equivalent of Ago2, with single and repeated Gαq stimulation whose trends were similar, but smaller than those seen with G3BP1 consistent the idea that ALG-1 stress granules are a subset of G3BP1 stress granules (18).…”

Section: Discussionmentioning

confidence: 99%

“…While stress granules form under adverse conditions, we also find that stress granules form when Gαq is activated. We have found that in PC12 cells, the stress granules that form as a result of Gαq activation sequester two specific mRNAs, a subunit of ATP synthase ( ATP5f1b ) and a protein that mediates vesicle formation ( Chgb ), in contrast to stress granules formed upon heat shock which sequester many different and non-specific RNAs (26). Because Gαq signaling is a normal physiological event in many species, it is possible that stress granules formed upon Gαq activation will accumulate if re-activation occurs before complete disassembly.…”

Section: Introductionmentioning

confidence: 99%

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Repeated Activation of Gαq by neurotransmitters causes age-dependent accumulation of stress granules inC.elegans

Rennie,

Scarlata

2023

Preprint

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Gαq proteins mediate signals from neurotransmitters to transduce calcium signals. In PC12 cells, we have shown that Gαq stimulation results in retraction of neurites and induces the formation of stress granules that sequester two specific mRNAs,ChbgbandATP5f1b. Here, we show that repeated activation of Gαq inC. elegansadversely reduces lifespan potentially through accumulation of stress granules and inefficient recovery from neurite retraction. In the absence of stimulation, we could not detect significant changes in number of stress granules from Day 1-15 worms. Single Gαq activation increases stress granule size through the enlargement of pre-formed particles with younger worms (Day 1-4) being more responsive than older (Day 8). Repeated Gαq stimulation impacts the number of particles through the assembly of nascent particles. Additionally, we a systematic rise in the number of AGL-1 stress granules with repeated Gαq stimulation suggesting that stress granules accumulate in neurons and sequester mRNAs. This idea is supported by immunofluorescence studies of ATP5f1b as well as changes in peristaltic speed. In addition to stress granule accumulation, we find that repeated Gαq activation results in age-dependent morphological defects in mechanosensory neurons. Taken together, studies show that repeated Gαq activation negatively influences the health ofC.elegans.

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“…Previous pull-down and mass spectrometry studies indicate that neither Egr-1 or TRBP are direct or indirect binding partners of PLCβ1 (29). However, TRBP is a component of Ago2 stress granules that form when cytosolic levels of PLCβ1 are lowered (30). We tested the idea that cytosolic PLCβ1 regulates the availability of TRBP for Egr-1 binding which may stabilize the cytosolic localization of Egr-1.…”

Section: Cytosolic Plcβ1 Regulates Egr-1 / Trbp Associationmentioning

confidence: 96%

PLCβ1 By-Passes Early Growth Response -1 to Induce and Maintain the Differentiation of Neuronal Cells

Scarlata,

González-Burguera,

Lin

et al. 2024

Preprint

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The Gαq/phospholipase C-β (PLCβ) signaling system mediates calcium responses to variety of hormones and neurotransmitters. Recent studies suggest that PLCβ1 expression plays a role in the differentiation of two types of cultured neuronal cells (PC12 and SKNSH) through a mechanism independent of Gαq. Here, we show a similar increase in PLCβ1 expression when human NT2 cells are induced to differentiate either through AraC or retinoic acid. Preventing this increase abolishes differentiation. Surprisingly, transfecting PLCβ1 into undifferentiated PC12 or NT2 cells induces differentiation without the need for differentiating agents. Studies to uncover the underlying mechanism focused on the transcription factor early growth response 1 (Egr-1) which mediates the expression of many proteins involved in differentiation including PLCb1. We find that increased levels of cytosolic PLCβ1 in undifferentiated PC12 and NT2 cells promote localization of Egr-1 to the nucleus. This shift to the nucleus is correlated disruption between Egr-1 and its cytosolic binding partner (Tar RNA binding protein) when PLCβ1 is over-expressed. These studies present a novel mechanism through which PLCβ1 can modulate differentiation.

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Activation of Gαq sequesters specific transcripts into Ago2 particles

Cited by 6 publications

References 42 publications

Unraveling Hidden Cell Signaling Pathways Using Biophysical Methods: Application to the Gαq/Phospholipase Cβ Signaling System

Unraveling Hidden Cell Signaling Pathways Using Biophysical Methods: Application to the Gαq/Phospholipase Cβ Signaling System

Repeated Activation of Gαq by neurotransmitters causes age-dependent accumulation of stress granules inC.elegans

PLCβ1 By-Passes Early Growth Response -1 to Induce and Maintain the Differentiation of Neuronal Cells

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