title: Regnase-1, a rapid response ribonuclease regulating inflammation and stress responses.
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.
authors.affiliation: Basic Medical Research Center, School of Medicine, Nantong University, Nantong, Jiangsu 226001, People's Republic of China.
authors.forename: Renfang
authors.initials: R
authors.lastname: Mao
authors.affiliation: Basic Medical Research Center, School of Medicine, Nantong University, Nantong, Jiangsu 226001, People's Republic of China.
authors.forename: Riyun
authors.initials: R
authors.lastname: Yang
authors.affiliation: Basic Medical Research Center, School of Medicine, Nantong University, Nantong, Jiangsu 226001, People's Republic of China.
authors.forename: Xia
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Edward W
authors.initials: EW
authors.lastname: Harhaj
authors.affiliation: Department of Immunology, School of Medicine, Nantong University, Nantong, Jiangsu 226001, People's Republic of China.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Wang
authors.affiliation: Basic Medical Research Center, School of Medicine, Nantong University, Nantong, Jiangsu 226001, People's Republic of China.|Department of Immunology, School of Medicine, Nantong University, Nantong, Jiangsu 226001, People's Republic of China.
authors.forename: Yihui
authors.initials: Y
authors.lastname: Fan
mesh_terms: D001327:Autoimmune Diseases / Q000503:physiopathology*; D006801:Humans; D007249:Inflammation / Q000503:physiopathology*; D012260:Ribonucleases / Q000378:metabolism*; D013312:Stress, Physiological; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D014157:Transcription Factors; D012260:Ribonucleases; C510646:ZC3H12A protein, human