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. 2020 Mar 17;52(3):542-556.e13.
doi: 10.1016/j.immuni.2020.02.007.

Dysregulated Expression of the Nuclear Exosome Targeting Complex Component Rbm7 in Nonhematopoietic Cells Licenses the Development of Fibrosis

Kiyoharu Fukushima  1 , Takashi Satoh  2 , Fuminori Sugihara  3 , Yuki Sato  4 , Toru Okamoto  5 , Yuichi Mitsui  1 , Sachiyo Yoshio  6 , Songling Li  7 , Satoshi Nojima  8 , Daisuke Motooka  9 , Shota Nakamura  9 , Hiroshi Kida  10 , Daron M Standley  7 , Eiichi Morii  8 , Tatsuya Kanto  6 , Motoko Yanagita  11 , Yoshiharu Matsuura  5 , Takashi Nagasawa  12 , Atsushi Kumanogoh  10 , Shizuo Akira  13
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Free article

Dysregulated Expression of the Nuclear Exosome Targeting Complex Component Rbm7 in Nonhematopoietic Cells Licenses the Development of Fibrosis

Kiyoharu Fukushima et al. Immunity. .
Free article

Abstract

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.

Keywords: RNA decay; fibrosis; innate immunity; macrophage; ncRNA.

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Conflict of interest statement

Declaration of Interests The authors declare competing financial interests: details are available in the online version of the paper. Readers are welcome to comment on the online version of the paper. Correspondence and requests for materials should be addressed to S.A. (sakira@biken.osaka-u.ac.jp) and T.S. (sohsatoh@biken.osaka-u.ac.jp).

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