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Capping protein regulator and myosin 1 linker 3 regulates transcription of key cytokines in activated phagocytic cells
Cellular Signalling ( IF 4.4 ) Pub Date : 2020-11-24 , DOI: 10.1016/j.cellsig.2020.109848
Na Zhao 1 , Wenjuan Dong 2 , Hajeong Kim 3 , Rezvan Moallemian 1 , Jiyang Lv 1 , Huan Wang 1 , Hua Zheng 1 , Fang Wei 1 , Xiaojing Ma 4
Affiliation  

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.



中文翻译:

帽蛋白调节剂和肌球蛋白 1 接头 3 调节活化吞噬细胞中关键细胞因子的转录

我们最近报道了帽蛋白调节剂和肌球蛋白 1 接头 3 (CARMIL3),首先被鉴定为一种癌胎样基因,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 作为吞噬凋亡细胞和/或暴露于脂多糖 (LPS) 的巨噬细胞中几种关键促炎细胞因子转录的重要调节剂的新功能。CARMIL3 缺陷的巨噬细胞响应 LPS,表达强烈降低的白细胞介素 (IL)-6、TNF-α、IL-1β 和 IL-23,而 IL-10 表达增强。对 LPS 刺激的 CARMIL3 缺陷型和野生型 (WT) RAW264.7 细胞的 RNA-seq 分析揭示了许多差异表达的基因,影响了几个重要的炎症通路。在分子水平上,CARMIL3 缺乏导致 LPS 激活的核因子-κB (NF-κB) 信号传导严重受损,IKKα/β 和 IκBα 磷酸化降低,p65 蛋白水平严重降低。这项研究揭示了 CARMIL3 在通过调节吞噬细胞中主要细胞因子的产生来影响炎症和组织稳态之间的平衡方面的关键作用。

更新日期:2020-12-03
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