Alternative splicing converts STIM2 from an activator to an inhibitor of store-operated calcium channels

Rana, Anshul; Yen, Michelle; Sadaghiani, Amir Masoud; Malmersjö, Seth; Park, Chan Young; Dolmetsch, Ricardo; Lewis, Richard S.

doi:10.1085/jgp.1461oia35

Cited by 21 publications

(43 citation statements)

References 53 publications

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“…The resulting protein STIM2.1 by itself is indeed unable to tightly bind and to activate Orai channels. While STIM2.1 shows a reduced expression compared with STIM2.2, we found relevant expression (nearly equal to STIM2.2) in naïve CD4 ϩ and CD8 ϩ T cells with significant downregulation of expression upon differentiation into effector cells (53), whereas Rana et al (63) found upregulation of the STIM2␤ (2.1) over STIM2␣ (2.2) upon early myogenic differentiation of murine C2C12 myoblasts. In naïve T cells, silencing of STIM2.1, but not of STIM2.2, caused an increase in SOCE, indicating a dominant-negative function of STIM2.1 in vivo.…”

Section: Alternative Splicingcontrasting

confidence: 60%

Changing calcium: CRAC channel (STIM and Orai) expression, splicing, and posttranslational modifiers

Niemeyer

2016

American Journal of Physiology-Cell Physiology

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A wide variety of cellular function depends on the dynamics of intracellular Ca(2+) signals. Especially for relatively slow and lasting processes such as gene expression, cell proliferation, and often migration, cells rely on the store-operated Ca(2+) entry (SOCE) pathway, which is particularly prominent in immune cells. SOCE is initiated by the sensor proteins (STIM1, STIM2) located within the endoplasmic reticulum (ER) registering the Ca(2+) concentration within the ER, and upon its depletion, cluster and trap Orai (Orai1-3) proteins located in the plasma membrane (PM) into ER-PM junctions. These regions become sites of highly selective Ca(2+) entry predominantly through Orai1-assembled channels, which, among other effector functions, is necessary for triggering NFAT translocation into the nucleus. What is less clear is how the spatial and temporal spread of intracellular Ca(2+) is shaped and regulated by differential expression of the individual SOCE genes and their splice variants, their heteromeric combinations and pre- and posttranslational modifications. This review focuses on principle mechanisms regulating expression, splicing, and targeting of Ca(2+) release-activated Ca(2+) (CRAC) channels.

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Section: Alternative Splicingcontrasting

confidence: 60%

Changing calcium: CRAC channel (STIM and Orai) expression, splicing, and posttranslational modifiers

Niemeyer

2016

American Journal of Physiology-Cell Physiology

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“…; Rana et al . ). On the other hand, bioinformatic tools predict the existence of four additional protein‐coding STIM2 mRNA isoforms in human (http://www.ensembl.org/).…”

Section: Introductionmentioning

confidence: 97%

“…; Rana et al . ), the interaction of STIM1 with TRPC Ca 2+ channels (Lee et al . ), as well as the communication with calmodulin (CaM) (Miederer et al .…”

Section: Introductionmentioning

confidence: 99%

Role of STIM2 in cell function and physiopathology

Berna‐Erro

Jardín

Salido

et al. 2017

The Journal of Physiology

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An endoplasmic reticulum (ER)-resident protein that regulates cytosolic and ER free-Ca concentration by induction of store-operated calcium entry: that is the original definition of STIM2 and its function. While its activity strongly depends on the amount of calcium stored in the ER, its function goes further, to intracellular signalling and gene expression. Initially under-studied owing to the prominent function of STIM1, STIM2 came to be regarded as vital in mice, gradually emerging as an important player in the nervous system, and cooperating with STIM1 in the immune system. STIM2 has also been proposed as a relevant player in pathological conditions related to ageing, Alzheimer's and Huntington's diseases, autoimmune disorders and cancer. The discovery of additional functions, together with new splicing forms with opposite roles, has clarified existing controversies about STIM2 function in SOCE. With STIM2 being essential for life, but apparently not for development, newly available data demonstrate a complex and still intriguing behaviour that this review summarizes, updating current knowledge of STIM2 function.

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“…The question we set out to explore was if all of these highly diverse functions of STIM1 are indeed mediated by exactly the same protein, or if and how alternative splicing modifies STIM1 structure and function to adapt to cell-type specific requirements. In the past, we and others have identified a splice variant of STIM2 (STIM2.1; STIM2ß), which prevents interaction and gating of Orai channels 16,17 thus acts as a strong dominant-negative regulator of SOCE by altering the density of activated Orai complexes 18 and has recently been shown to regulate myogenesis by controlling SOCE dependent transcriptional factors 19 . Given the existence of this inhibitory splice variant, the often small effects seen upon genetic deletion of STIM2 may indeed underestimate a STIM2 mediated effect, if the concomitant deletion of expressed STIM2.1 deletes the negative regulator STIM2.1/STIM2ß.…”

Section: Introductionmentioning

confidence: 99%

Alternative splicing switches STIM1 targeting to specialized membrane contact sites and modifies SOCE

Knapp

Förderer

Alansary

et al. 2020

Preprint

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Alternative splicing is a potent modifier of protein function. Stromal interaction molecule 1 (Stim1) is the essential activator molecule of store-operated Ca 2+ entry (SOCE) and a sorting regulator of certain ER proteins such as Stimulator of interferon genes (STING). Here, we characterize a conserved new variant, Stim1A, where splice-insertion translates into an additional C-terminal domain. We find prominent expression of exonA mRNA in testes, astrocytes, kidney and heart and confirm Stim1A protein in Western blot of testes. In situ, endogenous Stim1 with domain A, but not Stim1 without domain A localizes to unique adhesion junctions and to specialized membrane retrieval sites (tubulobulbar complexes) in testes. Functionally, using Ca 2+ imaging and patch-clamp analysis, Stim1A shows a dominant-negative effect on SOCE and I CRAC , despite normal clustering and interaction with Orai1 investigated by combined TIRF and FRET analyses and as confirmed by an increased SOCE upon knock-down of endogenous Stim1A in astrocytes. Mutational analyses in conjunction with imaging and patch-clamp analyses of residues either in domain A or within the N-terminal region of Orai1 demonstrate a specific defect in stabilized channel gating. Our findings demonstrate that celltype specific splicing of STIM1 adds both an intracellular targeting switch and adapts SOCE to meet the Ca 2+ requirements of specific subcellular contact sites. splicing | CRAC | membrane | endocytosis | gating | Sertoli | Orai | calcium | trafficking | variantCorrespondence: barbara.niemeyer@uks.eu

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Alternative splicing converts STIM2 from an activator to an inhibitor of store-operated calcium channels

Cited by 21 publications

References 53 publications

Changing calcium: CRAC channel (STIM and Orai) expression, splicing, and posttranslational modifiers

Changing calcium: CRAC channel (STIM and Orai) expression, splicing, and posttranslational modifiers

Role of STIM2 in cell function and physiopathology

Alternative splicing switches STIM1 targeting to specialized membrane contact sites and modifies SOCE

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