SRSF6 balances mitochondrial-driven innate immune outcomes through alternative splicing of BAX

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.

The following previously published data sets were used

Article and author information

Author details

  1. Allison R Wagner

    Texas A&M Health Science Center, Bryan, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Chi G Weindel

    Texas A&M Health Science Center, Bryan, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Kelsi O West

    Texas A&M Health Science Center, Bryan, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Haley M Scott

    Texas A&M Health Science Center, Bryan, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Robert O Watson

    Texas A&M Health Science Center, Bryan, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4976-0759
  6. Kristin L Patrick

    Texas A&M Health Science Center, Bryan, United States
    For correspondence
    kpatrick03@tamu.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2442-4679

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.

Reviewing Editor

  1. Kristen W Lynch, University of Pennsylvania, United States

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).

Version history

  1. Preprint posted: July 18, 2022 (view preprint)
  2. Received: July 28, 2022
  3. Accepted: November 20, 2022
  4. Accepted Manuscript published: November 21, 2022 (version 1)
  5. 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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  1. Allison R Wagner
  2. Chi G Weindel
  3. Kelsi O West
  4. Haley M Scott
  5. Robert O Watson
  6. Kristin L Patrick
(2022)
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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https://doi.org/10.7554/eLife.82244

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