Control of STIM and Orai function by post-translational modifications

Johnson, J. D.; Blackman, Rachel; Gross, Scott; Soboloff, Jonathan

doi:10.1016/j.ceca.2022.102544

Cited by 21 publications

(12 citation statements)

References 135 publications

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“…SOCE represents a ubiquitous signaling event observed in both excitable and non-excitable cells, serving as a linchpin in a myriad of physiological and pathophysiological responses 54 . Extensive studies have elucidated the multifaceted regulation of STIM through various post-translational modifications (PTMs), encompassing phosphorylation 55 , acylation 56,57 , glycosylation 18,19 , and oxidation by reactive oxygen species (ROS) 58,59 . Although the N-glycosylation of STIM1 was first reported in 2002 18 there has been a notable lack of further investigations into the potential involvement of deglycosylation enzymes in modulating STIM1 glycosylation over the past two decades.…”

Section: Discussionmentioning

confidence: 99%

Identification of Glucosidase II that regulates STIM1 activation dynamics

Du,

Zheng,

Wang

et al. 2024

Preprint

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The ubiquitous presence of stromal interaction molecule (STIM), endoplasmic reticulum (ER) Ca2+ sensors, plays a crucial role for maintaining Ca2+ homeostasis and signaling in mammalian cells by linking ER Ca2+ depletion with extracellular Ca2+ influx. Although recent advancements have shed light on glycosylation in STIM proteins, further exploration of deglycosylation enzyme modification and its role remains limited by methodological constraints. In this study, leveraging the miniTurbo-driven proximal biotinylation labeling method, we were able to screen for weak and transiently binding protein molecules within specific environments like ER lumina. Herein, we unveil glucosidase II, comprising GANAB and PRKCSH, as a novel partner of the STIM1 complex. Through investigations into Glucosidase II's (Glu II) regulation of STIM1's Ca2+ affinities both in cellulo and in situ, alongside its impact on store-operated Ca2+ entry (SOCE), we propose a novel mechanism wherein Glu II governs STIM1 activation by modulating Ca2+ binding affinity, thereby adjusting the level of activated STIM1 in response to physiological stimulation.

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Section: Discussionmentioning

confidence: 99%

Identification of Glucosidase II that regulates STIM1 activation dynamics

Du,

Zheng,

Wang

et al. 2024

Preprint

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“…CRAC is mainly composed of the STIM1-a transmembrane protein on the ER and the Orai1 protein, which is located on the cell membrane. STIM1 is mainly located in the ER with a small amount distributed in the cell membrane (47), and it is the most critical molecule mediating SOCE. Orai1, which is the most widely studied channel, coregulates SOCE with STIM1 (48).…”

Section: Discussionmentioning

confidence: 99%

HYDROGEN PREVENTS LIPOPOLYSACCHARIDE-INDUCED PULMONARY MICROVASCULAR ENDOTHELIAL CELL INJURY BY INHIBITING STORE-OPERATED Ca2+ ENTRY REGULATED BY STIM1/ORAI1

Li,

Chen,

Shu

et al. 2023

Shock

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Background Sepsis is a type of life-threatening organ dysfunction that is caused by a dysregulated host response to infection. The lung is the most vulnerable target organ under septic conditions. Pulmonary microvascular endothelial cells (PMVECs) play a critical role in acute lung injury (ALI) caused by severe sepsis. The impairment of PMVECs during sepsis is a complex regulatory process involving multiple mechanisms, in which the imbalance of calcium (Ca2+) homeostasis of endothelial cells is a key factor in its functional impairment. Our preliminary results indicated that hydrogen gas (H2) treatment significantly alleviates lung injury in sepsis, protects PMVECs from hyperpermeability, and decreases the expression of plasma membrane stromal interaction molecule 1 (STIM1), but the underlying mechanism by which H2 maintains Ca2+ homeostasis in endothelial cells in septic models remains unclear. Thus, the purpose of the present study was to investigate the molecular mechanism of STIM1 and Ca2+-release-activated- Ca2+ channel protein1 (Orai1) regulation by H2 treatment and explore the effect of H2 treatment on Ca2+ homeostasis in lipopolysaccharide (LPS)-induced PMVECs and LPS-challenged mice. Methods We observed the role of H2 on LPS-induced ALI of mice in vivo. The lung wet/dry (W/D) weight ratio, total protein in the bronchoalveolar lavage (BAL) fluid and Evans blue dye (EBD) assay were used to evaluate the pulmonary endothelial barrier damage of LPS-challenged mice. The expression of STIM1 and Orai1 were also detected using epifluorescence microscopy. Moreover, we also investigated the role of H2- rich medium in regulating PMVECs under LPS treatment, which induced injury similar to sepsis in vitro. The expression of STIM1 and Orai1 as well as the Ca2+ concentration in PMVECs were examined. Results In vivo, we found that H2 alleviated ALI of mice through decreasing lung W/D weight ratio, total protein in the BAL fluid and permeability of lung. In addition, H2 also decreased the expression of STIM1 and Orai1 in pulmonary microvascular endothelium. In vitro, LPS treatment increased the expression levels of STIM1 and Orai1 in PMVECs, while H2 reversed these changes. Furthermore, H2 ameliorated Ca2+ influx under sepsis-mimicking conditions. Treatment with the sarco/endoplasmic reticulum Ca2+ adenosine triphosphatase (SERCA) inhibitor, thapsigargin (TG), resulted in a significant reduction in cell viability as well as a reduction in the expression of junctional proteins, including VE-cadherin and occludin. Treatment with the store-operated Ca2+ entry (SOCE) inhibitor, YM-58483 (BTP2), increased the cell viability and expression of junctional proteins. Conclusions The present study suggested that H2 treatment alleviates LPS-induced PMVEC dysfunction by inhibiting SOCE mediated by STIM1 and Orai1 in vitro and in vivo.

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“…Despite the rapid growth in our understanding of the role of STIM and Orai and the widely accepted notion that they are core elements of a highly evolutionarily conserved Ca 2+ signaling pathway in all eukaryotes, numerous gaps in our knowledge remain. Such gaps include the understanding of the role of many post-translational modifications on the function ( Johnson et al, 2022 ). In addition, considerable uncertainty remains regarding the composition of the Orai channel itself, its regulation by STIM isoforms and little is known how this stoichiometry changes in response to aging or pathology.…”

Section: Discussionmentioning

confidence: 99%

STIM and Orai Mediated Regulation of Calcium Signaling in Age-Related Diseases

2022

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Tight spatiotemporal regulation of intracellular Ca2+ plays a critical role in regulating diverse cellular functions including cell survival, metabolism, and transcription. As a result, eukaryotic cells have developed a wide variety of mechanisms for controlling Ca2+ influx and efflux across the plasma membrane as well as Ca2+ release and uptake from intracellular stores. The STIM and Orai protein families comprising of STIM1, STIM2, Orai1, Orai2, and Orai3, are evolutionarily highly conserved proteins that are core components of all mammalian Ca2+ signaling systems. STIM1 and Orai1 are considered key players in the regulation of Store Operated Calcium Entry (SOCE), where release of Ca2+ from intracellular stores such as the Endoplasmic/Sarcoplasmic reticulum (ER/SR) triggers Ca2+ influx across the plasma membrane. SOCE, which has been widely characterized in non-excitable cells, plays a central role in Ca2+-dependent transcriptional regulation. In addition to their role in Ca2+ signaling, STIM1 and Orai1 have been shown to contribute to the regulation of metabolism and mitochondrial function. STIM and Orai proteins are also subject to redox modifications, which influence their activities. Considering their ubiquitous expression, there has been increasing interest in the roles of STIM and Orai proteins in excitable cells such as neurons and myocytes. While controversy remains as to the importance of SOCE in excitable cells, STIM1 and Orai1 are essential for cellular homeostasis and their disruption is linked to various diseases associated with aging such as cardiovascular disease and neurodegeneration. The recent identification of splice variants for most STIM and Orai isoforms while complicating our understanding of their function, may also provide insight into some of the current contradictions on their roles. Therefore, the goal of this review is to describe our current understanding of the molecular regulation of STIM and Orai proteins and their roles in normal physiology and diseases of aging, with a particular focus on heart disease and neurodegeneration.

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Control of STIM and Orai function by post-translational modifications

Cited by 21 publications

References 135 publications

Identification of Glucosidase II that regulates STIM1 activation dynamics

Identification of Glucosidase II that regulates STIM1 activation dynamics

HYDROGEN PREVENTS LIPOPOLYSACCHARIDE-INDUCED PULMONARY MICROVASCULAR ENDOTHELIAL CELL INJURY BY INHIBITING STORE-OPERATED Ca2+ ENTRY REGULATED BY STIM1/ORAI1

STIM and Orai Mediated Regulation of Calcium Signaling in Age-Related Diseases

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