부산대학교 도서관

T cell effector functions require sustained calcium influx. However, the signaling and phenotypic consequences of non-specific sodium permeation via calcium channels remain unknown. [alpha]-SNAP is a crucial component of Orai1 channels, and its depletion disrupts the functional assembly of Orai1 multimers. Here we show that [alpha]-SNAP hypomorph, hydrocephalus with hopping gait, Napa.sup.hyh/hyh mice harbor significant defects in CD4 T cell gene expression and Foxp3 regulatory T cell (Treg) differentiation. Mechanistically, TCR stimulation induced rapid sodium influx in Napa.sup.hyh/hyh CD4 T cells, which reduced intracellular ATP, [ATP].sub.i. Depletion of [ATP].sub.i inhibited mTORC2 dependent NF[kappa]B activation in Napa.sup.hyh/hyh cells but ablation of Orai1 restored it. Remarkably, TCR stimulation in the presence of monensin phenocopied the defects in Napa.sup.hyh/hyh signaling and Treg differentiation, but not IL-2 expression. Thus, non-specific sodium influx via bonafide calcium channels disrupts unexpected signaling nodes and may provide mechanistic insights into some divergent phenotypes associated with Orai1 function. DOI: http://dx.doi.org/10.7554/eLife.25155.001
Byline: Yong Miao, Jaya Bhushan, Adish Dani, Monika Vig Introduction A sustained rise in cytosolic calcium is necessary for nuclear translocation of calcium-dependent transcription factors such as nuclear factor of [...]