Regulation of Store-Operated Ca2+ Entry by SARAF

Dagan, Inbal; Palty, Raz

doi:10.3390/cells10081887

Cited by 10 publications

(7 citation statements)

References 138 publications

(312 reference statements)

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“…S1 M ). Consistent with the idea that SCDI arises from multiple mechanisms ( Dagan and Palty, 2021 ), this finding demonstrates unequivocally that although SARAF is an important factor for SCDI, it is not its sole mediator of this activity in HEK293 or Jurkat T cells. This conclusion is also supported by a recent report which showed that ANO-8 contributes to a distinct type of SARAF-independent SCDI in HEK293 cells ( Jha et al, 2019 ).…”

Section: Discussionsupporting

confidence: 86%

Bidirectional regulation of calcium release–activated calcium (CRAC) channel by SARAF

Zomot

Cohen

Dagan

et al. 2021

Journal of Cell Biology

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Store-operated calcium entry (SOCE) through the Ca2+ release–activated Ca2+ (CRAC) channel is a central mechanism by which cells generate Ca2+ signals and mediate Ca2+-dependent gene expression. The molecular basis for CRAC channel regulation by the SOCE-associated regulatory factor (SARAF) remained insufficiently understood. Here we found that following ER Ca2+ depletion, SARAF facilitates a conformational change in the ER Ca2+ sensor STIM1 that relieves an activation constraint enforced by the STIM1 inactivation domain (ID; aa 475–483) and promotes initial activation of STIM1, its translocation to ER–plasma membrane junctions, and coupling to Orai1 channels. Following intracellular Ca2+ rise, cooperation between SARAF and the STIM1 ID controls CRAC channel slow Ca2+-dependent inactivation. We further show that in T lymphocytes, SARAF is required for proper T cell receptor evoked transcription. Taking all these data together, we uncover a dual regulatory role for SARAF during both activation and inactivation of CRAC channels and show that SARAF fine-tunes intracellular Ca2+ responses and downstream gene expression in cells.

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Section: Discussionsupporting

confidence: 86%

Bidirectional regulation of calcium release–activated calcium (CRAC) channel by SARAF

Zomot

Cohen

Dagan

et al. 2021

Journal of Cell Biology

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“…1D, G). Similarly, SARAF, which 6 regulates STIM1 activity 37 , accumulated preferentially around myonuclei and at the NMJ (Fig. 1E, G).…”

Section: Genes Encoding Soce Components Display Regionalized Expressi...mentioning

confidence: 82%

mTORC1-dependent SOCE activity regulates synaptic gene expression and muscle response to denervation

Prola,

Dupont,

Rajendran

et al. 2024

Preprint

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Neuromuscular junction (NMJ) instability is central in muscle dysfunction occurring in neuromuscular disorders and aging. NMJ maintenance requires regionalized regulation of synaptic genes, previously associated with Ca2+-dependent pathways. However, what sustains Ca2+micro-domains in myofibers and allows a rapid response to denervation is not known. Here, we identify that Store-Operated Calcium Entry (SOCE) plays a critical role in synaptic gene regulation. SOCE components show differential enrichment in sub- and non-synaptic muscle regions. Especially, STIM1 accumulation at rough endoplasmic reticulum associates with functional SOCE at the endplate. Denervation increases SOCE in non- and sub- synaptic regions, together with reticulum remodeling.Stim1knockdown hampers denervation-induced synaptic gene up-regulation, while STIM1 overexpression increases synaptic gene expression in innervated muscle. Finally, mTORC1 activation mimics the effect of denervation on SOCE capacity, STIM1 localization and reticulum remodeling. Together, our results reveal a decisive role of SOCE in sensing innervation and regulating muscle response to denervation. They further suggest that SOCE perturbation may contribute to neuromuscular integrity loss in pathological conditions associated with mTORC1 dysregulation.

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“…As another perspective, the present model could be used to investigate how the increase in frequency of RYR1 opening observed ∼15 s after TCR/CD3 stimulation affects the spatiotemporal dynamics of junctional Ca 2+ during the transition of T cells towards full activation. In these longer time scales, additional aspects of SOCE regulation should be considered, such as slow Ca 2+ dependent inactivation ( Dagan and Palty, 2021 ) or the dynamic nature of the ER-PM junctions ( Okeke et al, 2016 ). The extension of the model to several junctions would enable to investigate how microdomains spread and interact to propagate Ca 2+ signals deeper into the cell and promote full activation.…”

Section: Discussionmentioning

confidence: 99%

Three-Dimensional Model of Sub-Plasmalemmal Ca2+ Microdomains Evoked by T Cell Receptor/CD3 Complex Stimulation

Gil

Diercks

Guse

et al. 2022

Front. Mol. Biosci.

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Ca2+ signalling plays an essential role in T cell activation, which is a key step to start an adaptive immune response. During the transition from a quiescent to a fully activated state, Ca2+ microdomains of reduced spatial and temporal extents develop in the junctions between the plasma membrane and the endoplasmic reticulum (ER). These microdomains rely on Ca2+ entry from the extracellular medium, via the ORAI1/STIM1/STIM2 system that mediates store operated Ca2+ entry Store operated calcium entry. The mechanism leading to local store depletion and subsequent Ca2+ entry depends on the activation state of the cells. The initial, smaller microdomains are triggered by D-myo-inositol 1,4,5-trisphosphate (IP3) signalling in response to T cell adhesion. T cell receptor (TCR)/CD3 stimulation then initiates nicotinic acid adenine dinucleotide phosphate signalling, which activates ryanodine receptors (RYR). We have recently developed a mathematical model to elucidate the spatiotemporal Ca2+ dynamics of the microdomains triggered by IP3 signalling in response to T cell adhesion (Gil et al., 2021). This reaction-diffusion model describes the evolution of the cytosolic and endoplasmic reticulum Ca2+ concentrations in a three-dimensional ER-PM junction and was solved using COMSOL Multiphysics. Modelling predicted that adhesion-dependent microdomains result from the concerted activity of IP3 receptors and pre-formed ORAI1-STIM2 complexes. In the present study, we extend this model to include the role of RYRs rapidly after TCR/CD3 stimulation. The involvement of STIM1, which has a lower KD for Ca2+ than STIM2, is also considered. Detailed 3D spatio-temporal simulations show that these Ca2+ microdomains rely on the concerted opening of ∼7 RYRs that are simultaneously active in response to the increase in NAADP induced by T cell stimulation. Opening of these RYRs provoke a local depletion of ER Ca2+ that triggers Ca2+ flux through the ORAI1 channels. Simulations predict that RYRs are most probably located around the junction and that the increase in junctional Ca2+ concentration results from the combination between diffusion of Ca2+ released through the RYRs and Ca2+ entry through ORAI1 in the junction. The computational model moreover provides a tool allowing to investigate how Ca2+ microdomains occur, extend and interact in various states of T cell activation.

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Regulation of Store-Operated Ca2+ Entry by SARAF

Cited by 10 publications

References 138 publications

Bidirectional regulation of calcium release–activated calcium (CRAC) channel by SARAF

Bidirectional regulation of calcium release–activated calcium (CRAC) channel by SARAF

mTORC1-dependent SOCE activity regulates synaptic gene expression and muscle response to denervation

Three-Dimensional Model of Sub-Plasmalemmal Ca2+ Microdomains Evoked by T Cell Receptor/CD3 Complex Stimulation

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