The E3 ubiquitin ligase RNF144B is LPS-inducible in human, but not mouse, macrophages and promotes inducible IL-1β expression
The E3 ubiquitin ligase RNF144B is LPS-inducible in human, but not mouse, macrophages and promotes inducible IL-1β expression
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DOI：
10.1189/jlb.2ab0815-339r
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发表时间：
2016-07-01
影响因子：
5.5
通讯作者：
Sweet, Matthew J.
中科院分区：
文献类型：
--
作者：
Ariffin, Juliana K.;Kapetanovic, Ronan;Sweet, Matthew J.
人类和小鼠免疫反应的差异可能部分反映了物种特异性适应，并可以为人类免疫提供重要见解。在本研究中，我们发现编码E3泛素连接酶的RNF144B在原代人巨噬细胞和人巨噬细胞样THP-1细胞中可被脂多糖诱导。相比之下，Rnf144b在几种小鼠细胞群中不能被脂多糖诱导，包括来自C57BL/6和BALB/c小鼠的原代巨噬细胞和RAW264.7巨噬细胞。同样，Rnf144b在大肠杆菌感染C57BL/6小鼠后也没有上调。尽管人和小鼠的RNF144B基因都有保守的转录起始位点，但基因表达数据的cap分析证实，RNF144B启动子在人而不是小鼠巨噬细胞中指导转录。人和小鼠的RNF144B基因由高度保守的含有tata的启动子控制，但转录因子结合位点的细微差异可能解释了差异调控。通过基因沉默，我们发现RNF144B对于在原代人巨噬细胞中引发炎性小体反应是必需的。具体来说，RNF144B促进脂多糖诱导的IL-1b mRNA表达，但不调节其他几种脂多糖诱导的细胞因子（如白介素-10、干扰素- γ）的表达，也不影响炎性体成分或底物（如procaspase-1、pro-interleukin-18）的表达。因此，我们的发现揭示了人类巨噬细胞中选择性炎性体启动的物种特异性调节机制。
Differences in human and mouse immune responses may partly reflect species-specific adaptations and can provide important insights into human immunity. In this study, we show that RNF144B, which encodes an E3 ubiquitin ligase, was lipopolysaccharide-inducible in primary human macrophages and in human macrophage-like THP-1 cells. In contrast, Rnf144b was not lipopolysaccharide-inducible in several mouse cell populations, including primary macrophages from C57BL/6 and BALB/c mice and RAW264.7 macrophages. Similarly, Rnf144b was not up-regulated by infection of C57BL/6 mice with Escherichia coli. Although the human and mouse RNF144B genes have conserved transcription start sites, cap analysis of gene expression data confirmed that the RNF144B promoter directs transcription in human but not mouse macrophages. The human andmouse RNF144B genes are controlled by highly conserved TATA-containing promoters, but subtle differences in transcription factor binding sites may account for differential regulation. Using gene silencing, we showed that RNF144B is necessary for priming of inflammasome responses in primary human macrophages. Specifically, RNF144B promotes lipopolysaccharide-inducible IL-1b mRNA expression but does not regulate expression of several other lipopolysaccharide-inducible cytokines (e.g., interleukin-10, interferon-gamma) or affect expression of inflammasome components or substrates (e.g., procaspase-1, pro-interleukin-18). Our findings thus revealed a species-specific regulatory mechanism for selective inflammasome priming in human macrophages.