Na+ influx via Orai1 inhibits intracellular ATP induced mTORC2 signaling to disrupt CD4 T cell gene expression and differentiation

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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, 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 NFB 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.

Data availability

The following data sets were generated

1. Vig M
(2017) Data from Na+ Influx via Orai1 Inhibits Intracellular ATP Induced mTORC2 Signaling To Disrupt CD4 T Cell Gene Expression and Differentiation
Available at Dryad Digital Repository under a CC0 Public Domain Dedication.

http://dx.doi.org/10.5061/dryad.202fn

Article and author information

Author details

Yong Miao

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States

Competing interests
The authors declare that no competing interests exist.
Jaya Bhushan

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States

Competing interests
The authors declare that no competing interests exist.
Adish Dani

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-5491-7709
Monika Vig

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States

For correspondence
mvig@WUSTL.EDU

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-4770-8853

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

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.