Orai3 and Orai1 mediate CRAC channel function and metabolic reprogramming in B cells
- Pennsylvania State University, United States
- New York University Langone Medical Center, United States
- University of Pittsburgh, United States
Abstract
The essential role of store-operated Ca2+ entry (SOCE) through Ca2+ release-activated Ca2+ (CRAC) channels in T cells is well established. In contrast, the contribution of individual Orai isoforms to SOCE and their downstream signaling functions in B cells are poorly understood. Here, we demonstrate changes in expression of Orai isoforms in response to B cell activation. We show that both Orai3 and Orai1 mediate native CRAC channels in B cells. The combined loss of Orai1 and Orai3, but not Orai3 alone, impairs SOCE, proliferation and survival, nuclear factor of activated T cells (NFAT) activation, mitochondrial respiration, glycolysis, and the metabolic reprogramming of primary B cells in response to antigenic stimulation. Nevertheless, combined deletion of Orai1 and Orai3 in B cells did not compromise humoral immunity to influenza A virus infection in mice, suggesting that other in vivo co-stimulatory signals can overcome the requirement of BCR-mediated CRAC channel function in B cells. Our results shed important new light on the physiological roles of Orai1 and Orai3 proteins in SOCE and effector functions of B lymphocytes.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting file
Article and author information
Author details
Funding
National Heart, Lung, and Blood Institute (R35-HL150778)
- Mohamed Trebak
National Institute of Allergy and Infectious Diseases (R01-AI162971)
- Ziaur SM Rahman
National Institute of Allergy and Infectious Diseases (R01-AI097302 and R01-AI130143)
- Stefan Feske
National Institute of Allergy and Infectious Diseases (F30-AI164803-01)
- Anthony Y Tao
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Murali Prakriya, Northwestern University, United States
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols of Penn State University: Protocols #: 46290, 47477, and 47350
Version history
- Preprint posted: May 6, 2022 (view preprint)
- Received: November 6, 2022
- Accepted: February 16, 2023
- Accepted Manuscript published: February 21, 2023 (version 1)
- Version of Record published: March 9, 2023 (version 2)
Copyright
© 2023, Emrich 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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Orai3 and Orai1 mediate CRAC channel function and metabolic reprogramming in B cells
eLife 12:e84708.
https://doi.org/10.7554/eLife.84708
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