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, 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 NFκB 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.

DOI: http://dx.doi.org/10.7554/eLife.25155.001

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Most cited references 61

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A mutation in Orai1 causes immune deficiency by abrogating CRAC channel function.

Stefan Feske, Yousang Gwack, Murali Prakriya … (2006)

Antigen stimulation of immune cells triggers Ca2+ entry through Ca2+ release-activated Ca2+ (CRAC) channels, promoting the immune response to pathogens by activating the transcription factor NFAT. We have previously shown that cells from patients with one form of hereditary severe combined immune deficiency (SCID) syndrome are defective in store-operated Ca2+ entry and CRAC channel function. Here we identify the genetic defect in these patients, using a combination of two unbiased genome-wide approaches: a modified linkage analysis with single-nucleotide polymorphism arrays, and a Drosophila RNA interference screen designed to identify regulators of store-operated Ca2+ entry and NFAT nuclear import. Both approaches converged on a novel protein that we call Orai1, which contains four putative transmembrane segments. The SCID patients are homozygous for a single missense mutation in ORAI1, and expression of wild-type Orai1 in SCID T cells restores store-operated Ca2+ influx and the CRAC current (I(CRAC)). We propose that Orai1 is an essential component or regulator of the CRAC channel complex.

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Store-operated calcium channels.

Anant B. Parekh, James W. Putney (2005)

In electrically nonexcitable cells, Ca(2+) influx is essential for regulating a host of kinetically distinct processes involving exocytosis, enzyme control, gene regulation, cell growth and proliferation, and apoptosis. The major Ca(2+) entry pathway in these cells is the store-operated one, in which the emptying of intracellular Ca(2+) stores activates Ca(2+) influx (store-operated Ca(2+) entry, or capacitative Ca(2+) entry). Several biophysically distinct store-operated currents have been reported, but the best characterized is the Ca(2+) release-activated Ca(2+) current, I(CRAC). Although it was initially considered to function only in nonexcitable cells, growing evidence now points towards a central role for I(CRAC)-like currents in excitable cells too. In spite of intense research, the signal that relays the store Ca(2+) content to CRAC channels in the plasma membrane, as well as the molecular identity of the Ca(2+) sensor within the stores, remains elusive. Resolution of these issues would be greatly helped by the identification of the CRAC channel gene. In some systems, evidence suggests that store-operated channels might be related to TRP homologs, although no consensus has yet been reached. Better understood are mechanisms that inactivate store-operated entry and hence control the overall duration of Ca(2+) entry. Recent work has revealed a central role for mitochondria in the regulation of I(CRAC), and this is particularly prominent under physiological conditions. I(CRAC) therefore represents a dynamic interplay between endoplasmic reticulum, mitochondria, and plasma membrane. In this review, we describe the key electrophysiological features of I(CRAC) and other store-operated Ca(2+) currents and how they are regulated, and we consider recent advances that have shed insight into the molecular mechanisms involved in this ubiquitous and vital Ca(2+) entry pathway.

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CRACM1 is a plasma membrane protein essential for store-operated Ca2+ entry.

M Vig, C. Peinelt, A. Beck … (2006)

Store-operated Ca2+ entry is mediated by Ca2+ release-activated Ca2+ (CRAC) channels following Ca2+ release from intracellular stores. We performed a genome-wide RNA interference (RNAi) screen in Drosophila cells to identify proteins that inhibit store-operated Ca2+ influx. A secondary patch-clamp screen identified CRACM1 and CRACM2 (CRAC modulators 1 and 2) as modulators of Drosophila CRAC currents. We characterized the human ortholog of CRACM1, a plasma membrane-resident protein encoded by gene FLJ14466. Although overexpression of CRACM1 did not affect CRAC currents, RNAi-mediated knockdown disrupted its activation. CRACM1 could be the CRAC channel itself, a subunit of it, or a component of the CRAC signaling machinery.

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Author and article information

Contributors

Shimon Sakaguchi: Role: Reviewing editor

Journal

Journal ID (nlm-ta): eLife

Journal ID (iso-abbrev): Elife

Journal ID (hwp): eLife

Journal ID (publisher-id): eLife

Title: eLife

Publisher: eLife Sciences Publications, Ltd

ISSN (Electronic): 2050-084X

Publication date (Electronic, pub): 11 May 2017

Publication date Collection: 2017

Volume: 6

Electronic Location Identifier: e25155

Affiliations

[1 ]deptDepartment of Pathology and Immunology , Washington University School of Medicine , St Louis, United States

[2 ]deptHope Center for Neurological Disorders , Washington University School of Medicine , St Louis, United States

Osaka University , Japan

Author notes

mvig@ 123456WUSTL.EDU

Author information

Yong Miao http://orcid.org/0000-0003-2614-1445

Adish Dani http://orcid.org/0000-0002-5491-7709

Monika Vig http://orcid.org/0000-0002-4770-8853

Article

Publisher ID: 25155

DOI: 10.7554/eLife.25155

PMC ID: 5459575

PubMed ID: 28492364

SO-VID: b7684e23-1b00-4fbc-bb69-5a54be4b8590

License:

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

History

Date received : 16 January 2017

Date accepted : 10 May 2017

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100000048, American Cancer Society;

Award ID: ACS-RSG 14-040-01-CSM

Award Recipient : Monika Vig

Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;

Award ID: AI108636

Award Recipient : Monika Vig

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Custom metadata

elife-xml-version 2.5

Author impact statement Non-specific sodium entry inhibits T cell receptor induced gene expression and differentiation of T cells by depleting intracellular ATP and disrupting mTORC2 dependent signalling axis.

ScienceOpen disciplines: Life sciences

Keywords: sodium influx,orai,atp,foxp3 t cell,calcium channel,mtorc,mouse

Data availability:

ScienceOpen disciplines: Life sciences

Keywords: sodium influx, orai, atp, foxp3 t cell, calcium channel, mtorc, mouse

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