title: Control of type I interferon-induced cell death by Orai1-mediated calcium entry in T cells.
abstract: Store-operated Ca(2+) entry (SOCE) is an essential process in T cell activation. SOCE is controlled by the Ca(2+) release-activated Ca(2+) (CRAC) channel encoded by the gene Orai1 that is expressed on the plasma membrane and activated by STIM1 when ER Ca(2+) stores are depleted. Our earlier work showed that a somatic T-cell line Jurkat mutant H123 bearing a defect in Ca(2+) signaling was susceptible to the apoptotic effects of type I interferons (IFN-α/β). The nature of the mutation and whether this mutation was linked to IFN-α/β apoptotic susceptibility was unknown. Here we show that H123 cells lacked Orai1 and exhibit reduced STIM1 protein. Reconstitution of both Orai1 and STIM1 in H123 cells rescued SOCE in response to thapsigargin and ionomycin and abrogated IFN-α/β-induced apoptosis. Reciprocally, overexpression of the dominant negative Orai1-E106A in either parental Jurkat cells or an unrelated human T cell line (CEM391) inhibited SOCE and led to sensitization to IFN-α/β-induced apoptosis. Furthermore, we showed that the Ca(2+) response pathway antagonized the IFN-α/β -induced transcriptional responses; in the absence of SOCE, this negative regulatory effect was lost. However, the inhibitory effect of Ca(2+) on type I IFN-induced gene transcription was diminished by pharmacological inhibition of NF-κB in cells with intact SOCE. Our findings reveal an unexpected and novel regulatory crosstalk mechanism between type I IFNs and store-operated Ca(2+) signaling pathways mediated at least in part by NF-κB activity with significant clinical implications to both viral and tumor immunology.
authors.affiliation: Department of Biochemistry, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
authors.forename: Chanyu
authors.initials: C
authors.lastname: Yue
authors.forename: Jonathan
authors.initials: J
authors.lastname: Soboloff
authors.forename: Ana M
authors.initials: AM
authors.lastname: Gamero
mesh_terms: D019943:Amino Acid Substitution; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D016923:Cell Death / Q000235:genetics; D045744:Cell Line, Tumor; D006801:Humans; D016898:Interferon-alpha / Q000235:genetics / Q000378:metabolism*; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism*; D020125:Mutation, Missense; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D000071740:ORAI1 Protein; D013601:T-Lymphocytes / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology
chemical_list: D015220:Calcium Channels; D016898:Interferon-alpha; D016328:NF-kappa B; D000071740:ORAI1 Protein; C510746:ORAI1 protein, human; D016899:Interferon-beta