| First Author | Miao Y | Year | 2017 |
| Journal | Elife | Volume | 6 |
| PubMed ID | 28492364 | Mgi Jnum | J:257150 |
| Mgi Id | MGI:6116974 | Doi | 10.7554/eLife.25155 |
| Citation | Miao Y, et al. (2017) Na(+) influx via Orai1 inhibits intracellular ATP-induced mTORC2 signaling to disrupt CD4 T cell gene expression and differentiation. Elife 6:e25155 |
| abstractText | 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(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(hyh/hyh) CD4 T cells, which reduced intracellular ATP, [ATP]i. Depletion of [ATP]i inhibited mTORC2 dependent NFkappaB activation in Napa(hyh/hyh) cells but ablation of Orai1 restored it. Remarkably, TCR stimulation in the presence of monensin phenocopied the defects in Napa(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. |
