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 Ⅱ-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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