SRSF6 balances mitochondrial-driven innate immune outcomes through alternative splicing of BAX
- Texas A&M Health Science Center, United States
Abstract
To mount a protective response to infection while preventing hyperinflammation, gene expression in innate immune cells must be tightly regulated. Despite the importance of pre-mRNA splicing in shaping the proteome, its role in balancing immune outcomes remains understudied. Transcriptomic analysis of murine macrophage cell lines identified Serine/Arginine Rich Splicing factor 6 (SRSF6) as a gatekeeper of mitochondrial homeostasis. SRSF6-dependent orchestration of mitochondrial health is directed in large part by alternative splicing of the pro-apoptosis pore-forming protein BAX. Loss of SRSF6 promotes accumulation of BAX-k, a variant that sensitizes macrophages to undergo cell death and triggers upregulation of interferon stimulated genes through cGAS sensing of cytosolic mitochondrial DNA. Upon pathogen sensing, macrophages regulate SRSF6 expression to control the liberation of immunogenic mtDNA and adjust the threshold for entry into programmed cell death. This work defines BAX alternative splicing by SRSF6 as a critical node not only in mitochondrial homeostasis, but also in the macrophage’s response to pathogens.
Data availability
Sequencing data have been deposited in GEO under accession code GSE171418. All other data generated or analyzed during this study are included in the manuscript and supporting files.
Article and author information
Author details
Funding
National Institutes of Health (R35GM133720)
- Kristin L Patrick
National Institutes of Health (R01AI125512)
- Robert O Watson
- Kristin L Patrick
National Institutes of Health (F31GM143893)
- Haley M Scott
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 experiments for this study were reviewed and approved by the Texas A&M University Institutional Animal Care and Use Committee (AUP# 2019-0083).
Reviewing Editor
- Kristen W Lynch, University of Pennsylvania, United States
Version history
- Preprint posted: July 18, 2022 (view preprint)
- Received: July 28, 2022
- Accepted: November 20, 2022
- Accepted Manuscript published: November 21, 2022 (version 1)
- Version of Record published: December 2, 2022 (version 2)
Copyright
© 2022, Wagner 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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SRSF6 balances mitochondrial-driven innate immune outcomes through alternative splicing of BAX
eLife 11:e82244.
https://doi.org/10.7554/eLife.82244
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