Capping protein regulator and myosin 1 linker 3 regulates transcription of key cytokines in activated phagocytic cells
Capping protein regulator and myosin 1 linker 3 regulates transcription of key cytokines in activated phagocytic cells
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加帽蛋白调节剂和肌球蛋白 1 连接子 3 调节活化吞噬细胞中关键细胞因子的转录
DOI：
10.1016/j.cellsig.2020.109848
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Xiaojing Ma
中科院分区：
文献类型：
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作者：
Na Zhao;Wenjuan Dong;Hajeong Kim;Rezvan Moallemian;Jiyang Lv;Huan Wang;Hua Zheng;Fang Wei;Xiaojing Ma
我们最近报道了封盖蛋白调节因子和肌球蛋白1连接子3 (CARMIL3)，首次被发现是一个癌样基因，通过调节质膜附近的肌动蛋白细胞骨架动力学，是乳腺癌和前列腺癌细胞转移所必需的。在这里，我们证明了CARMIL3作为巨噬细胞吞噬凋亡细胞和/或暴露于脂多糖（LPS）中的几种关键促炎细胞因子转录的重要调节因子的新功能。carmil3缺失的巨噬细胞在LPS作用下表达的白细胞介素(IL)-6、TNF-α、IL-1β和IL-23水平明显降低，而IL-10的表达则增强。对carmil3缺陷和野生型（WT） RAW264.7细胞进行RNA-seq分析，发现LPS刺激下存在许多差异表达基因，影响了几种重要的炎症途径。在分子水平上，CARMIL3缺失导致lps激活的核因子-κB （NF-κB）信号通路严重受损，IKKα/β和i -κB α磷酸化降低，p65蛋白水平严重降低。本研究揭示了CARMIL3通过调节吞噬细胞中主要细胞因子的产生，在影响炎症和组织稳态平衡中的重要作用。
We have recently reported that capping protein regulator and myosin 1 linker 3 (CARMIL3), first identified as an oncofetal-like gene, is required for metastasis of breast and prostate cancer cells via regulating the actin cytoskeletal dynamics near the plasma membrane. Here, we demonstrate a novel function of CARMIL3 as an essential regulator of the transcription of several key proinflammatory cytokines in macrophages engulfing apoptotic cells and/or exposed to lipopolysaccharides (LPS). CARMIL3-deficient macrophages expressed strongly abrogated levels of interleukin (IL)-6, TNF-α, IL-1β and IL-23 in response to LPS, whereas IL-10 expression was enhanced. An RNA-seq analysis of CARMIL3-deficient and wild-type (WT) RAW264.7 cells stimulated with LPS revealed many differentially expressed genes, impacting several important inflammatory pathways. At the molecular level, CARMIL3 deficiency caused a strong impairment in LPS-activated nuclear factor-κB (NF-κB) signaling with decreased IKKα/β and IκBα phosphorylation and severely reduced p65 protein levels. This study uncovers a crucial role of CARMIL3 in impacting the balance between inflammation and tissue homeostasis via regulating major cytokines production in phagocytic cells.