Dysregulated Expression of the Nuclear Exosome Targeting Complex Component Rbm7 in Nonhematopoietic Cells Licenses the Development of Fibrosis
Dysregulated Expression of the Nuclear Exosome Targeting Complex Component Rbm7 in Nonhematopoietic Cells Licenses the Development of Fibrosis
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DOI：
10.1016/j.immuni.2020.02.007
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发表时间：
2020-03-17
期刊：
影响因子：
32.4
通讯作者：
Akira, Shizuo
中科院分区：
文献类型：
--
作者：
Fukushima, Kiyoharu;Satoh, Takashi;Akira, Shizuo
纤维化是一种病因不明的无法治愈的疾病。含核分离的非典型单核细胞(SATM)在纤维化的发生发展中起重要作用。在这里，我们研究了向纤维化前区域招募SATM的机制。基于细胞因子在纤维化肺中表达的筛查显示，由凋亡的非造血细胞产生的趋化因子CXCL12对于SATM的募集是必不可少的。对纤维化开始时的肺组织的分析显示，Rbm7的表达增加，这是核外体靶向复合体的一种成分。Rbm7缺失抑制了博莱霉素诱导的纤维化，并在细胞水平上抑制了非造血细胞的凋亡。从机械上讲，Rbm7与形成亚核体的非编码(NC)RNA结合，包括Neat1斑点。Rbm7的异常表达导致Neat1斑点的核降解，DNA修复蛋白BRCA1的弥散，并触发细胞凋亡。因此，上皮细胞中的Rbm7通过调节ncRNA的衰变，从而调节趋化因子的产生，在纤维化的发展中发挥关键作用。
Fibrosis is an incurable disorder of unknown etiology. Segregated-nucleus-containing atypical monocytes (SatMs) are critical for the development of fibrosis. Here we examined the mechanisms that recruit SatMs to pre-fibrotic areas. A screen based on cytokine expression in the fibrotic lung revealed that the chemokine Cxcl12, which is produced by apoptotic nonhematopoietic cells, was essential for SatM recruitment. Analyses of lung tissues at fibrosis onset showed increased expression of Rbm7, a component of the nuclear exosome targeting complex. Rbm7 deletion suppressed bleomycin-induced fibrosis and at a cellular level, suppressed apoptosis of nonhematopoietic cells. Mechanistically, Rbm7 bound to noncoding (nc)RNAs that form subnuclear bodies, including Neat1 speckles. Dysregulated expression of Rbm7 resulted in the nuclear degradation of Neat1 speckles, the dispersion of the DNA repair protein BRCA1, and the triggering of apoptosis. Thus, Rbm7 in epithelial cells plays a critical role in the development of fibrosis by regulating ncRNA decay and thereby the production of chemokines that recruit SatMs.