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STIM1 and calcium control the transcriptional networks regulating T-bet expression and Th1 differentiation

ABSTRACT: The ER Ca2+ sensor STIM1 is critical for store-operated Ca2+ entry (SOCE) through ORAI1 Ca2+ channels, which play important roles in nuclear factor of activated T cells (NFAT) activation and T cell function. Loss-of-function (LOF) mutations in STIM1 or ORAI1 cause severe immunodeficiency with recurrent infections caused by viral and other pathogens. T helper 1 (Th1) cells, which express the transcription factor T-bet (encoded by TBX21) and produce interferon (IFN) g, are critical for immunity to intracellular pathogens. The role of STIM1 and SOCE in Th1 differentiation and the underlying mechanisms are not well understood. Here, we report a patient with an intronic mutation in STIM1 that creates a de novo splice acceptor site, leads to STIM1 mRNA degradation and loss of STIM1 protein expression. STIM1 deficiency abolishes SOCE upon TCR stimulation and prevents the expression of Th1 cell-specific genes, including TBX21 and IFNG. Mechanistically, STIM1 controls the binding of NFAT to the distal region of the TBX21 enhancer. NFAT synergizes with signal transducer and activator of transcription 1 (STAT1), which is activated by IFN-g produced by activated T cells, to initiate the transcription of the TBX21 gene. Unexpectedly, STIM1 deficiency sensitizes T cells to interleukin 12 (IL-12) signaling by increasing the expression of IL-12 receptors, and exogenous IL-12 rescues TBX21 expression and Th1 differentiation in STIM1-deficient T cells. Our study reveals how the STIM1-SOCE-NFAT axis differentially regulates the transcriptional networks that control TBX21 expression and Th1 differentiation under IL-12-dependent and independent conditions.

ORGANISM(S): Mus musculus

PROVIDER: GSE253187 | GEO | 2025/01/01

REPOSITORIES: GEO

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Project description:Systemic lupus erythematous (SLE) is a prototype of autoimmune disease. Lupus nephritis (LN) is one of the most serious complications of SLE. The development of autoreactive B cells and the production of autoantibodies have been critical for the initiation and progression of LN. Store-operated Ca2+ entry (SOCE) is the main Ca2+ influx pathway in lymphocytes and is essential for immune response . SOCE is mediated by Ca2+ release-activated Ca2+ (CRAC) channels which are comprised of stromal interaction molecule (STIM) and calcium release-activated calcium modulators (ORAI) . Mutations in genes encoding the CRAC channel abolish SOCE in cells of the immune system and cause severe combined immunodeficiency . Calcium signaling via ORAI1 has been involved in the pathogenesis of autoimmune diseases by driving Th17 differentiation . STIM1 deficiency significantly reduced Th1/Th17 responses and resulted in complete protection from experimental autoimmune encephalomyelitis . Compared to T cells, the roles of CRAC channel in B cells is far less clear. Ca²⁺/calmodulin (CaM)-dependent protein kinase2 (CaMK2) is a serine/threonine-specific protein kinase that is regulated by the Ca²⁺/CaM complex. CaMK2 has been involved in many signaling pathways and is necessary for Ca²⁺ homeostasis, T cell development and activation. CaMK4, another member of the CaMK family, has been shown to compromises podocyte function and promote renal diseases in LN. In the current study, we found that CRAC channel mediated calcium signaling is enhanced in B cells from patients with LN. CRAC channel inhibition by YM-58483 and knocked down of CRAC channel by ORAI1 or STIM2 siRNA led to suppression of CaMK2 signaling and decreased B cell differentiation. Lupus mice treated with CRAC channel inhibitor showed reduced anti-double stranded DNA antibodies (anti-dsDNA), decreased immune deposition in the glomeruli and improved renal function. CRAC channel mediates the development and progression of LN by promoting the differentiation of B cells into plasma cells.

Project description:STIM1 is an endoplasmic reticulum (ER) calcium (Ca2+) sensor that serves to replenish ER Ca2+ stores in response to ER Ca2+ depletion through gating of plasmalemmal Orai1 channels in a process known as store operated calcium entry (SOCE). Previously, we have shown that SOCE is impaired in the diabetic pancreatic β cell; however, the consequences of reduced β cell SOCE have not been well studied. To test this, we generated mice with pancreatic β cell specific deletion of STIM1 (STIM1Δβ). Our results revealed a striking sexual dimorphism in metabolic phenotypes when STIM1Δβ mice were challenged with high fat diet for 8 weeks. Male STIM1Δβ mice showed no differences in total weight, lean or fat mass, or glucose tolerance compared to WT littermate controls. In contrast, female STIM1Δβ mice displayed significantly increased total body weight, fat mass, and reduced glucose tolerance, in vivo glucose-stimulated insulin secretion and β cell mass compared to WT littermate controls, while insulin sensitivity, food intake, and energy expenditure were unchanged. To investigate mechanisms underlying these findings, RNA sequencing was performed in isolated islets and revealed altered 17-beta estradiol (E2) signaling, lipid metabolism, epithelial cell differentiation and decreased noncanonical estradiol receptor GPER. Consistent with this, alpha cell mass was increased in female STIM1Δβ, while proteomics and immunoblot analysis of STIM1 knockout (STIM1KO) INS-1 beta cells revealed reduce insulin expression and increased glucagon expression, suggesting STIM1 may be required for the maintenance of β cell identity. To this end, we show that a reduction of a noncanonical estradiol receptor GPER in STIM1 deficient islets contributes to the marked sexual dimorphism observed during beta cell dysfunction in female STIM1Δβ mice. This present study delineates a sexually dimorphic regulation of STIM1 in the maintenance of pancreatic beta cell identity through GPER and may expand the field of therapeutic approaches to diabetes. Our findings demonstrate the importance of STIM1 and GPER expression stability in the anti-diabetogenic response from estradiol.

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STIM1 and calcium control the transcriptional networks regulating T-bet expression and Th1 differentiation

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