ORAI1 establishes resistance to SARS-CoV-2 infection by regulating tonic type I interferon levels
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA726809 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14385317.fastq.gz | Fastqsanger.gz | |||
| SRR14385318.fastq.gz | Fastqsanger.gz | |||
| SRR14385319.fastq.gz | Fastqsanger.gz | |||
| SRR14385320.fastq.gz | Fastqsanger.gz | |||
| SRR14385321.fastq.gz | Fastqsanger.gz |
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Project description:We report RNAseq analysis of control, ORAI1KO and STIM1 KO (knockout) HEK293-ACE2 cells under uninfected (mock) and SARS-CoV-2-infected conditions
2021-05-20 | GSE173707 | GEO
Project description:ORAI1 and STIM1 are the critical mediators of store-operated Ca 2+ entry by acting as the pore subunit and an endoplasmic reticulum-resident signaling molecule, respectively. In addition to Ca 2+ signaling, STIM1 is also involved in regulation of a cytosolic nucleic acid sensing pathway. Using ORAI1 and STIM1 knockout cells, we examined their contribution to the host response to SARS-CoV-2 infection. STIM1 knockout cells showed strong resistance to SARS-CoV-2 infection due to enhanced type I interferon response. On the contrary, ORAI1 knockout cells showed high susceptibility to SARS-CoV-2 infection as judged by increased expression of viral proteins and a high viral load. Mechanistically, ORAI1 knockout cells showed reduced homeostatic cytoplasmic Ca 2+ concentration and severe impairment in tonic interferon signaling. Transcriptome analysis showed downregulation of multiple cellular defense mechanisms, including antiviral signaling pathways in ORAI1 knockout cells, which are likely due to reduced expression of the Ca 2+ -dependent transcription factors of the activator protein 1 (AP-1) family and MEF2C . Our results identify a novel role of ORAI1-mediated Ca 2+ signaling in regulating the baseline type I interferon level, which is a determinant of host resistance to SARS-CoV-2 infection.
| S-EPMC8109209 | biostudies-literature
Project description:Positive selection occurs in the thymic cortex, but critical maturation events occur later in the medulla. We defined the precise stage at which T cells acquire competence to proliferate and emigrate. Transcriptome analysis of late gene changes suggested roles for NF-κB and interferon signaling. Mice lacking the IKK kinase TAK1, showed normal positive selection, but a specific block in functional maturation. NF-κB signaling provided protection from TNF, and was required for proliferation and emigration. Alternatively, the interferon signature was independent of NF-κB, and IFNαR deficient thymocytes showed reduced STAT1 levels and phenotypic abnormality, but were competent to proliferate. Thus, both NF-κB and tonic IFN signals are involved in the final maturation of thymocytes into naïve T cells. Gene expression profile was performed on cells isolated from mouse thymus, including Pre-DP, Post-DP, SM&M1, M2 and Tak1-deficient SM&M1 cells.
2016-04-03 | E-GEOD-74078 | biostudies-arrayexpress
Project description:Oral cancer causes pain associated with cancer progression. The mechanism(s) underlying the pain is not fully understood. We report here that the function of the Ca2+ channel ORAI1 is an important regulator of oral cancer pain. ORAI1 was highly expressed in tumor samples from oral cancer patients and ORAI1 activation caused sustained Ca2+ influx in human oral cancer cells. RNA-seq analysis showed broad modulation of oral cancer markers such MMPs and pain modulators by ORAI1. Inoculation of oral cancer cells lacking ORAI1 into mouse paws reduced ectopic tumor growth and allodynia, reducing secreted MMP1 levels and the excitation of trigeminal ganglia (TG) neurons. The stimulation of TG neurons with MMP1 evoked an increase in action potentials. These data demonstrate an important role of ORAI1 in oral cancer progression likely by controlling the expression of MMP1 resulting in increased cancer progression and pain
2023-12-27 | GSE236706 | GEO
Project description:Platelet-derived growth factor (PDGF) signalling and the subsequent activation of the calcium ion channel, ORAI1 are critical drivers of pathological remodelling of native vascular smooth muscle cells to proliferative state, which is a process associated with various vascular diseases. This study aims to reveal transcriptional networks altered following ORAI1 inhibition in vascular smooth muscle cells. To study the effect of ORAI1 inhibition on VSMC biology, we performed RNA-Seq analysis of PDGF-stimulated primary human aortic smooth muscle cells treated with either ORAI1 inhibitor, (n=4) or with vehicle (n=4), and investigated the effect of ORAI1 inhibition on the transcriptional response of cells.
2023-09-21 | E-MTAB-10955 | biostudies-arrayexpress
Project description:Positive selection occurs in the thymic cortex, but critical maturation events occur later in the medulla. We defined the precise stage at which T cells acquire competence to proliferate and emigrate. Transcriptome analysis of late gene changes suggested roles for NF-κB and interferon signaling. Mice lacking the IKK kinase TAK1, showed normal positive selection, but a specific block in functional maturation. NF-κB signaling provided protection from TNF, and was required for proliferation and emigration. Alternatively, the interferon signature was independent of NF-κB, and IFNαR deficient thymocytes showed reduced STAT1 levels and phenotypic abnormality, but were competent to proliferate. Thus, both NF-κB and tonic IFN signals are involved in the final maturation of thymocytes into naïve T cells.
2016-04-03 | GSE74078 | GEO
Project description:ORAI1 and stromal interaction molecule 1 (STIM1) are the critical mediators of store-operated Ca2+ entry by acting as the pore subunit and an endoplasmic reticulum-resident signaling molecule, respectively. In addition to Ca2+ signaling, STIM1 is also involved in regulation of the type I IFN (IFN-I) response. To examine their potential role in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, we generated ORAI1 and STIM1 knockout human HEK293-angiotensin-converting enzyme 2 cells and checked their responses. STIM1 knockout cells showed strong resistance to SARS-CoV-2 infection as a result of enhanced IFN-I response. On the contrary, ORAI1 deletion induced high susceptibility to SARS-CoV-2 infection. Mechanistically, ORAI1 knockout cells showed reduced homeostatic cytoplasmic Ca2+ concentration and severe impairment in tonic IFN-I signaling. Transcriptome analysis showed downregulation of multiple antiviral signaling pathways in ORAI1 knockout cells, likely because of reduced expression of the Ca2+-dependent transcription factors of the AP-1 family and MEF2C Accordingly, modulation of homeostatic Ca2+ concentration by pretreatment with ORAI1 blocker or agonist could influence baseline IFNB expression and resistance to SARS-CoV-2 infection in a human lung epithelial cell line. Our results identify a novel role of ORAI1-mediated Ca2+ signaling in regulating the tonic IFN-I levels, which determine host resistance to SARS-CoV-2 infection.
| S-EPMC8702473 | biostudies-literature
Project description:We showed that the overexpression of ORAI1 in the neurons of murine brain leads to spontaneous occurrence of seizure-like events in aged animals. We aimed to identify the mechanism responsible for this phenomenon. Using modified Ca2+-addback assay in the slices of CA1 hippocampal region and FURA-2AM calcium indicator we found that overexpression of ORAI1 in neurons leads to altered Ca2+ response. Next, by RNASeq we identified set of genes, whose expression was changed in FVB/NJ-Tg(ORAI1)Ibd mice.
2019-12-17 | GSE138370 | GEO
Project description:Tubular aggregate myopathy (TAM) and Stormorken syndrome (STRMK) are clinically overlapping disorders characterized by childhood-onset muscle weakness and a variable occurrence of multi-systemic signs including short stature, thrombocytopenia, and hyposplenism. TAM/STRMK is caused by gain-of-function mutations in the Ca2+ sensor STIM1 or the Ca2+ channel ORAI1, both regulating Ca2+ homeostasis through the ubiquitous SOCE (store-operated Ca2+ entry) mechanism. Functional experiments in cells have demonstrated that the TAM/STRMK mutations induce SOCE overactivation, resulting in excessive influx of extracellular Ca2+. There is currently no treatment for TAM/STRMK, but SOCE is amenable to manipulation. Here we crossed Stim1R304W/+ mice harboring the most common TAM/STRMK mutation with Orai1R93W/+ mice carrying an ORAI1 mutation partially obstructing Ca2+ influx. Compared with Stim1R304W/+ littermates, Stim1R304W/+Orai1R93W/+ offspring showed a normalization of bone architecture, spleen histology, and muscle morphology, an increase of thrombocytes, and improved muscle contraction and relaxation kinetics. Accordingly, comparative RNA- sequencing detected more than 1200 dysregulated genes in Stim1R304W/+ mice and revealed a major restoration of gene expression in Stim1R304W/+Orai1R93W/+ mice. Altogether, we provide physiological, morphological, functional, and molecular data highlighting the therapeutic potential of ORAI1 inhibition to rescue the multi-systemic TAM/STRMK signs, and we identified myostatin as a suitable biomarker for TAM/STRMK in human and mouse.
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Project description:The strength of the T cell receptor interaction with self-ligands affects antigen-specific immune responses. However, the precise role, functional relationship, and underlying mechanisms have not been elucidated completely. Here, we demonstrate that naive CD8+ T cells with relatively high self-reactivity are phenotypically heterogeneous owing to varied responses to type I interferon (T1IFN), resulting in three distinct subsets, CD5loLy6C–, CD5hiLy6C–, and CD5hiLy6C+ cells. CD5hiLy6C+ cells differ from CD5loLy6C– and CD5hiLy6C– cells in their gene expression profiles and functional properties. Moreover, CD5hiLy6C+ cells demonstrate more extensive antigen-specific expansion upon viral infection, with enhanced differentiation into terminal effector cells and reduced memory cell generation. Such unique features of CD5hiLy6C+ cells are imprinted in a steady-state and observed even for those of monoclonal CD8+ T cell populations in a T1IFN dependent fashion. These findings demonstrate that self-reactivity shapes the functional diversity of naive CD8+ T cells by co-opting tonic T1IFN signaling.
2021-06-19 | GSE178445 | GEO