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.

Data availability

The following data sets were generated

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.

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.

Metrics

  • 1,836
    views
  • 331
    downloads
  • 9
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Share this article

https://doi.org/10.7554/eLife.25155

Further reading

    1. Immunology and Inflammation
    2. Microbiology and Infectious Disease
    Xu Zheng, Shi Yu ... Guangxun Meng
    Research Article

    Innate immune responses triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection play pivotal roles in the pathogenesis of COVID-19, while host factors including proinflammatory cytokines are critical for viral containment. By utilizing quantitative and qualitative models, we discovered that soluble factors secreted by human monocytes potently inhibit SARS-CoV-2-induced cell-cell fusion in viral-infected cells. Through cytokine screening, we identified that interleukin-1β (IL-1β), a key mediator of inflammation, inhibits syncytia formation mediated by various SARS-CoV-2 strains. Mechanistically, IL-1β activates RhoA/ROCK signaling through a non-canonical IL-1 receptor-dependent pathway, which drives the enrichment of actin bundles at the cell-cell junctions, thus prevents syncytia formation. Notably, in vivo infection experiments in mice confirmed that IL-1β significantly restricted SARS-CoV-2 spread in the lung epithelium. Together, by revealing the function and underlying mechanism of IL-1β on SARS-CoV-2-induced cell-cell fusion, our study highlights an unprecedented antiviral function for cytokines during viral infection.

    1. Immunology and Inflammation
    Ning Song, Hang Gao ... Wenlong Zhang
    Research Article

    Gout is a prevalent form of inflammatory arthritis that occurs due to high levels of uric acid in the blood leading to the formation of urate crystals in and around the joints, particularly affecting the elderly. Recent research has provided evidence of distinct differences in the gut microbiota of patients with gout and hyperuricemia compared to healthy individuals. However, the link between gut microbiota and age-related gout remained underexplored. Our study found that gut microbiota plays a crucial role in determining susceptibility to age-related gout. Specifically, we observed that age-related gut microbiota regulated the activation of the NLRP3 inflammasome pathway and modulated uric acid metabolism. More scrutiny highlighted the positive impact of ‘younger’ microbiota on the gut microbiota structure of old or aged mice, enhancing butanoate metabolism and butyric acid content. Experimentation with butyrate supplementation indicated that butyric acid exerts a dual effect, inhibiting inflammation in acute gout and reducing serum uric acid levels. These insights emphasize the potential of gut microbiome rejuvenation in mitigating senile gout, unraveling the intricate dynamics between microbiota, aging, and gout. It potentially serves as a therapeutic target for senile gout-related conditions.