SRSF6 balances mitochondrial-driven innate immune outcomes through alternative splicing of BAX.
SRSF6 balances mitochondrial-driven innate immune outcomes through alternative splicing of BAX.
复制标题
DOI：
10.7554/elife.82244
复制
发表时间：
2022-11-21
期刊：
影响因子：
7.7
通讯作者：
Patrick KL
中科院分区：
文献类型：
--
作者：
Wagner AR;Weindel CG;West KO;Scott HM;Watson RO;Patrick KL
为了对感染产生保护性反应，同时防止过度炎症，必须严格调节先天免疫细胞中的基因表达。尽管前mrna剪接在形成蛋白质组中的重要性，但其在平衡免疫结果中的作用仍未得到充分研究。小鼠巨噬细胞系的转录组学分析发现，丝氨酸/精氨酸富剪接因子6 （SRSF6）是线粒体稳态的守门人。依赖srsf6的线粒体健康调控在很大程度上是由促凋亡孔形成蛋白BAX的选择性剪接所引导的。SRSF6的缺失促进BAX-κ的积累，BAX-κ是一种使巨噬细胞敏化并经历细胞死亡的变体，并通过cGAS感知细胞质线粒体DNA触发干扰素刺激基因的上调。巨噬细胞感知病原体后，通过调控SRSF6的表达来控制免疫原性mtDNA的释放，调节进入程序性细胞死亡的门槛。这项工作将SRSF6的BAX选择性剪接定义为一个关键节点，不仅在线粒体稳态中，而且在巨噬细胞对病原体的反应中。
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-κ, 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.
影响因子：
--
作者：
Abebe M;Kim L;Rook G;Aseffa A;Wassie L;Zewdie M;Zumla A;Engers H;Andersen P;Doherty TM
通讯作者：
Doherty TM