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.

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).

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.

Metrics

  • 1,676
    views
  • 207
    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. 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

Share this article

https://doi.org/10.7554/eLife.82244

Further reading

    1. Chromosomes and Gene Expression
    Shihui Chen, Carolyn Marie Phillips
    Research Article

    RNA interference (RNAi) is a conserved pathway that utilizes Argonaute proteins and their associated small RNAs to exert gene regulatory function on complementary transcripts. While the majority of germline-expressed RNAi proteins reside in perinuclear germ granules, it is unknown whether and how RNAi pathways are spatially organized in other cell types. Here, we find that the small RNA biogenesis machinery is spatially and temporally organized during Caenorhabditis elegans embryogenesis. Specifically, the RNAi factor, SIMR-1, forms visible concentrates during mid-embryogenesis that contain an RNA-dependent RNA polymerase, a poly-UG polymerase, and the unloaded nuclear Argonaute protein, NRDE-3. Curiously, coincident with the appearance of the SIMR granules, the small RNAs bound to NRDE-3 switch from predominantly CSR-class 22G-RNAs to ERGO-dependent 22G-RNAs. NRDE-3 binds ERGO-dependent 22G-RNAs in the somatic cells of larvae and adults to silence ERGO-target genes; here we further demonstrate that NRDE-3-bound, CSR-class 22G-RNAs repress transcription in oocytes. Thus, our study defines two separable roles for NRDE-3, targeting germline-expressed genes during oogenesis to promote global transcriptional repression, and switching during embryogenesis to repress recently duplicated genes and retrotransposons in somatic cells, highlighting the plasticity of Argonaute proteins and the need for more precise temporal characterization of Argonaute-small RNA interactions.

    1. Chromosomes and Gene Expression
    2. Genetics and Genomics
    Steven Henikoff, David L Levens
    Insight

    A new method for mapping torsion provides insights into the ways that the genome responds to the torsion generated by RNA polymerase II.