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Regnase-1, a rapid response ribonuclease regulating inflammation and stress responses

Cellular & Molecular Immunology volume 14, pages 412–422 (2017)Cite this article

Abstract

RNA-binding proteins (RBPs) are central players in post-transcriptional regulation and immune homeostasis. The ribonuclease and RBP Regnase-1 exerts critical roles in both immune cells and non-immune cells. Its expression is rapidly induced under diverse conditions including microbial infections, treatment with inflammatory cytokines and chemical or mechanical stimulation. Regnase-1 activation is transient and is subject to negative feedback mechanisms including proteasome-mediated degradation or mucosa-associated lymphoid tissue 1 (MALT1) mediated cleavage. The major function of Regnase-1 is promoting mRNA decay via its ribonuclease activity by specifically targeting a subset of genes in different cell types. In monocytes, Regnase-1 downregulates IL-6 and IL-12B mRNAs, thus mitigating inflammation, whereas in T cells, it restricts T-cell activation by targeting c-Rel, Ox40 and Il-2 transcripts. In cancer cells, Regnase-1 promotes apoptosis by inhibiting anti-apoptotic genes including Bcl2L1, Bcl2A1, RelB and Bcl3. Together with up-frameshift protein-1 (UPF1), Regnase-1 specifically cleaves mRNAs that are active during translation by recognizing a stem-loop (SL) structure within the 3′UTRs of these genes in endoplasmic reticulum-bound ribosomes. Through this mechanism, Regnase-1 rapidly shapes mRNA profiles and associated protein expression, restricts inflammation and maintains immune homeostasis. Dysregulation of Regnase-1 has been described in a multitude of pathological states including autoimmune diseases, cancer and cardiovascular diseases. Here, we provide a comprehensive update on the function, regulation and molecular mechanisms of Regnase-1, and we propose that Regnase-1 may function as a master rapid response gene for cellular adaption triggered by microenvironmental changes.

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Acknowledgements

This work was supported by the Distinguished Professorship Program of Jiangsu Province to YF; the National Natural Science Foundation of China (81641164; 81600386; 81471539 and 30801350); and the Natural Science Foundation of Jiangsu Province (BK20141236). EWH is supported by NIH grants RO1CA135362 and R21AI112763. We apologize to the many scientists who made contributions to the field but have not been cited because of space limitations.

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Authors and Affiliations

  1. Basic Medical Research Center, School of Medicine, Nantong University, Nantong, Jiangsu 226001, People’s Republic of China

    Renfang Mao, Riyun Yang, Xia Chen & Yihui Fan

  2. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA

    Edward W Harhaj

  3. Department of Immunology, School of Medicine, Nantong University, Nantong, Jiangsu 226001, People’s Republic of China

    Xiaoying Wang & Yihui Fan

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  1. Renfang Mao
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  2. Riyun Yang
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  3. Xia Chen
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  4. Edward W Harhaj
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  5. Xiaoying Wang
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Correspondence to Yihui Fan.

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Mao, R., Yang, R., Chen, X. et al. Regnase-1, a rapid response ribonuclease regulating inflammation and stress responses. Cell Mol Immunol 14, 412–422 (2017). https://doi.org/10.1038/cmi.2016.70

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