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

  1. Yong Miao
  2. Jaya Bhushan
  3. Adish Dani
  4. Monika Vig  Is a corresponding author
  1. 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 NFB 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.

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Article and author information

Author details

  1. 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.
  2. 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.
  3. 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.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5491-7709
  4. 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.
    ORCID icon "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.

Reviewing Editor

  1. Shimon Sakaguchi, Osaka University, Japan

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.

Version history

  1. Received: January 16, 2017
  2. Accepted: May 10, 2017
  3. Accepted Manuscript published: May 11, 2017 (version 1)
  4. Accepted Manuscript updated: May 31, 2017 (version 2)
  5. Version of Record published: June 5, 2017 (version 3)

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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  1. Yong Miao
  2. Jaya Bhushan
  3. Adish Dani
  4. Monika Vig
(2017)
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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https://doi.org/10.7554/eLife.25155

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