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.

Splicing Factor PQBP1 Curtails BAX Expression to Promote Ovarian Cancer Progression

“…[ 31 ] A recent study reported that SRSF6 deletion promotes the retention of BAX intron 1 to generate BAX‐k, an isoform that sensitizes macrophages to undergo apoptosis. [ 32 ] In the present study, we demonstrated that PQBP1 knockdown promoted exon 2 inclusion to generate BAX‐L. In contrast, ectopic expression of PQBP1 promoted BAX exon 2 skipping and led to a premature termination codon and to a truncated isoform that underwent nonsense‐mediated decay.…”

Serine/arginine-rich splicing factor 7 promotes the type I interferon response by activating Irf7 transcription

“…To pinpoint where in the type I IFN signaling response SRSF7 acts, we treated Srsf7 KD or SCR RAW MΦs with LPS and measured secretion of IFN-β/α over a 6 h time course via an ISRE-luciferase reporter cell line. 11 , 42 Srsf7 KD MΦs produced significantly less IFN-β/α compared to SCR controls at all time points measured ( Figure 3A ). We next asked if impaired ISG expression in Srsf7 KD MΦs could be rescued if Srsf7 KD and SCR control cells received equal amounts of recombinant IFN-β.…”

“… 8 – 10 We recently implicated SRSF6 in maintaining mitochondrial homeostasis and antiviral immunity in MΦs by controlling AS of the pro-apoptotic factor BAX. 11 …”

Alternative splicing and related RNA binding proteins in human health and disease

“…Upon pathogen detection, macrophages modulate SRSF6 expression to control the release of immunogenic mtDNA and adjust the threshold for initiating programmed cell death. 140 QKI-5 plays a role in macrophage differentiation. 141 During the progression of atherosclerosis, QKI-5 serves as a dynamic regulator of ASE and expression profiles, driving monocyte activation, adhesion, and differentiation into macrophages, thereby contributing to disease progression.…”