日本大阪大学Shizuo Akira和Takashi Satoh研究团队合作发现,非造血细胞中核外泌体靶向复合物组分Rbm7的表达失调导致纤维化的发展。这一研究成果发表在2020年3月17日出版的《免疫学》上。
纤维化是一种病因不明的无法治愈疾病,SatMs对于纤维化的发展至关重要。
在本研究中,研究人员揭示了将含有分离核的非典型性单核细胞(SatMs)招募到纤维化前区的机制。基于肺纤维化中细胞因子表达的筛选显示,由凋亡非造血细胞产生的趋化因子Cxcl12对于SatM招募至关重要。
纤维化发生时对肺组织的分析显示Rbm7的表达增加,Rbm7是核外泌体靶向复合物的组分。敲出Rbm7抑制了博来霉素诱导的纤维化,并在细胞水平上抑制非造血细胞的凋亡。
从机制上看,Rbm7与形成亚核小体(包括Neat1斑点)的非编码(nc)RNA结合。 Rbm7表达失调导致Neat1斑点的核降解、DNA修复蛋白BRCA1的分解和细胞凋亡的发生。
因此,上皮细胞中的Rbm7通过调控ncRNA降解来产生招募SatMs的趋化因子,从而在纤维化的发展中起关键作用。
附:英文原文
Title: Dysregulated Expression of the Nuclear Exosome Targeting Complex Component Rbm7 in Nonhematopoietic Cells Licenses the Development of Fibrosis
Author: Kiyoharu Fukushima, Takashi Satoh, Fuminori Sugihara, Yuki Sato, Toru Okamoto, Yuichi Mitsui, Sachiyo Yoshio, Songling Li, Satoshi Nojima, Daisuke Motooka, Shota Nakamura, Hiroshi Kida, Daron M. Standley, Eiichi Morii, Tatsuya Kanto, Motoko Yanagita, Yoshiharu Matsuura, Takashi Nagasawa, Atsushi Kumanogoh, Shizuo Akira
Issue&Volume: 2020/03/17
Abstract: Fibrosis is an incurable disorder of unknown etiology. Segregated-nucleus-containingatypical monocytes (SatMs) are critical for the development of fibrosis. Here we examinedthe mechanisms that recruit SatMs to pre-fibrotic areas. A screen based on cytokineexpression in the fibrotic lung revealed that the chemokine Cxcl12, which is producedby apoptotic nonhematopoietic cells, was essential for SatM recruitment. Analysesof lung tissues at fibrosis onset showed increased expression of Rbm7, a componentof the nuclear exosome targeting complex. Rbm7 deletion suppressed bleomycin-induced fibrosis and at a cellular level, suppressedapoptosis of nonhematopoietic cells. Mechanistically, Rbm7 bound to noncoding (nc)RNAsthat form subnuclear bodies, including Neat1 speckles. Dysregulated expression of Rbm7 resulted in the nuclear degradation ofNeat1 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 fibrosisby regulating ncRNA decay and thereby the production of chemokines that recruit SatMs.
DOI: 10.1016/j.immuni.2020.02.007
Source: https://www.cell.com/immunity/fulltext/S1074-7613(20)30078-9
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