Na+ influx via Orai1 inhibits intracellular ATP induced mTORC2 signaling to disrupt CD4 T cell gene expression and differentiation
- Washington University School of Medicine, United States
Abstract
T cell effector functions require sustained calcium influx. However, the signaling and phenotypic consequences of non-specific sodium permeation via calcium channels remain unknown. α-SNAP is a crucial component of Orai1 channels, and its depletion disrupts the functional assembly of Orai1 multimers. Here we show that α-SNAP hypomorph, hydrocephalos with hopping gait, Napahyh/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 Napahyh/hyh CD4 T cells, which reduced intracellular ATP, [ATP]i. Depletion of [ATP]i inhibited mTORC2 dependent NFB activation in Napahyh/hyh cells but ablation of Orai1 restored it. Remarkably, TCR stimulation in the presence of monensin phenocopied the defects in Napahyh/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.
Data availability
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Data from Na+ Influx via Orai1 Inhibits Intracellular ATP Induced mTORC2 Signaling To Disrupt CD4 T Cell Gene Expression and DifferentiationAvailable at Dryad Digital Repository under a CC0 Public Domain Dedication.
Article and author information
Author details
Funding
American Cancer Society (ACS-RSG 14-040-01-CSM)
- Yong Miao
National Institutes of Health (AI108636)
- Yong Miao
- Jaya Bhushan
- Adish Dani
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal experiments were performed according to the guidelines of the Animal Studies Committee of the Washington University School of Medicine in Saint Louis, Protocol Approval Number 20150289.
Copyright
© 2017, Miao et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Na+ influx via Orai1 inhibits intracellular ATP induced mTORC2 signaling to disrupt CD4 T cell gene expression and differentiation
eLife 6:e25155.
https://doi.org/10.7554/eLife.25155
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