title: mRNA degradation by the endoribonuclease Regnase-1/ZC3H12a/MCPIP-1.
abstract: Post-transcriptional regulation is a crucial step for coordinating immune responses. Post-transcriptional mechanisms exquisitely control inflammation by increasing or decreasing both the stability of mRNAs and the efficiency of protein translation. Regulatory RNase 1 (Regnase-1, also known as Zc3h12a or MCPIP1) was identified as a novel protein harboring a CCCH-type zinc-finger domain and a PIN-like RNase domain. Regnase-1 mRNA expression is induced by Toll-like receptor (TLR) ligands, interleukin (IL)-1β and MCP-1. Regnase-1 destabilizes mRNAs encoding immune related proteins including IL-6 and IL-12p40 via their 3' untranslated regions. In Regnase-1-deficient (-/-) macrophages, IL-6 is overproduced in response to LPS because Il6 mRNA is stabilized because of Regnase-1 deficiency. Regnase-1(-/-) mice developed severe systemic inflammation, characterized by production of autoantibodies. It is now known that Regnase-1 protein expression is dynamically regulated during the course of inflammation. Upon IL-1β and TLR stimulation, Regnase-1 is rapidly phosphorylated by IκB kinases (IKKs) and degraded via ubiquitin-proteasome machinery. Regnase-1 degradation allows Il6 mRNA to be expressed rapidly and robustly upon stimulation. Furthermore, Regnase-1 destabilizes its own mRNA, thereby preventing excessive translation of Regnase-1 and degradation of cytokine-encoding mRNAs. In this review, we will discuss the mechanism of Regnase-1-mediated mRNA decay and describe the mechanism by which Regnase-1 is tightly regulated in innate immune cells. This article is part of a Special Issue entitled: RNA Decay mechanisms.
authors.affiliation: Laboratory of Host Defense, WPI Immunology Frontier Research Center, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Uehata
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
mesh_terms: D000818:Animals; D007113:Immunity, Innate / Q000235:genetics; D053583:Interleukin-1beta / Q000378:metabolism; D008024:Ligands; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D017434:Protein Structure, Tertiary; D020871:RNA Stability / Q000235:genetics*; D012260:Ribonucleases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism
chemical_list: D053583:Interleukin-1beta; D008024:Ligands; D012260:Ribonucleases; D051193:Toll-Like Receptors; C541320:Zc3h12a protein, mouse