The splicing factor SRSF6 controls Mycobacterium tuberculosis replication through its role in maintaining mitochondrial homeostasis Academic Article uri icon


  • Abstract Macrophages are the primary host cell that supports the survival and replication of the intracellular bacterial pathogen Mycobacterium tuberculosis (Mtb). We are interested in how macrophage proteins are functionalized during Mtb infection. Global proteomics analysis of Mtb-infected primary macrophages found that many RNA binding proteins of the Serine/Arginine rich splicing family (SRSF) can be differentially phosphorylated, suggesting that these factors regulate splicing decisions during Mtb infection. Knockdown of one such SRSF protein, called SR6, results in basal upregulation of interferon stimulated genes (ISGs) in macrophages. We hypothesized that this phenotype was driven by mitochondrial damage that leaks mitochondria DNA into the cytosol and activates cGAS. Consistent with this idea, we measured increased mitochondrial stress and increased cell death in SR6 KD macrophages. Transcriptomics analysis of these cells revealed upregulation of an alternatively spliced (AS) isoform of the apoptotic factor BAX, which contributes to mitochondrial dysfunction, mtDNA release, and basal ISG expression. While BAX isoforms are known to regulate cell death, this is the first report of BAX AS regulating the type I IFN response. Lastly, we found that SR6 KD macrophages are permissive to Mtb replication, suggesting that controlling cell death at the level of BAX isoform abundance is an important but unappreciated component of the macrophage antibacterial repertoire. Together, our data support a model whereby SR6-dependent AS of Bax triggers mitochondria stress causing mtDNA leakage and type I IFN expression, metabolic dysfunction that primes cells to undergo cell death, and increased susceptibility to Mtb infection.

published proceedings

  • The Journal of Immunology

author list (cited authors)

  • Wagner, A., Weindel, C., West, K., Watson, R., & Patrick, K.

citation count

  • 0

complete list of authors

  • Wagner, Allison||Weindel, Chi||West, Kelsi||Watson, Robert||Patrick, Kristin

publication date

  • May 2022