S-1

Gene expression is controlled at multiple points, including signal transduction, transcription and mRNA stability. So far, transcriptional regulation has been extensively studied. However, recent studies have revealed that control of gene expression at the mRNA level is as important as transcriptional control in the immune response. The innate immune system is an evolutionally conserved host defense mechanism against pathogens. Innate immune responses are initiated by activation of pattern recognition receptors (PRRs), which recognize microbial components. Among them, Toll-like receptors (TLRs) are capable of sensing organisms ranging from bacteria to fungi, protozoa and viruses, and play a major role in innate immunity. Individual TLRs recognize different microbial components, activate different signaling pathways via selective usage of adaptor molecules, and give rise to different patterns in gene expression. We are now focusing on the role of genes induced in response to TLR stimulation, particularly the genes that are rapidly induced in a MyD88-dependent manner within 30min after LPS stimulation. Among them, we have recently identified a novel gene named Zc3h12a which has a CCCH-type zinc finger domain. The knockout mice developed spontaneous autoimmune diseases accompanied by splenomegaly and lymphadenopathy. Subsequent studies showed that Zc3h12a is a nuclease involved in destabilization of IL-6 and IL-12mRNA via the stem loop structure present in the 3’UTR of these genes. We renamed it Regulatory RNase-1 (Regnase-1) based on the function. I would like to discuss the role of Regnase-1 in the immune response.