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

• Published in: 中国免疫学杂志：英文版 Vol. 14; no. 5; pp. 412 - 422
• Main Author: Renfang Mao Riyun Yang Xia Chen Edward W Harhaj Xiaoying Wang Yihui Fan
• Format: Journal Article
• Language: English
• Published: 2017
• Subjects: RNA结合蛋白; 免疫细胞; 应激反应; 快速反应; 核糖核酸酶; 炎症反应; 自身免疫性疾病; 转录后调控
• ISSN: 1672-7681; 2042-0226

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 11-2 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.