Osamu Takeuchi M.D., PhD

Osamu Takeuchi M.D., Ph.D. is a professor in the Graduate School of Medicine, Kyoto University. After receiving M.D. from Osaka University and clinical training, he entered graduate school of medicine, Osaka University, where he started working on innate immunity with Prof. Shizuo Akira. Takeuchi discovered that different Toll-like receptors (TLRs) recognize different microbial components, and received Ph.D. degree. He subsequently completed postdoctoral training at Dana-Farber Cancer Institute under Prof. Stan Korsmeyer. Then he became an assistant professor in Osaka University, and worked on functional roles of TLR signaling molecules and RIG-I-like receptors in inflammation. In 2012, he moved to Institute for Frontier Life and Medical Sciences, Kyoto University as a full professor. He is currently focusing on the posttranscriptional regulation of inflammation by a set of RNA binding proteins.

Takeuchi received JSPS (Japan Society for the Promotion of Science) Prize and Japan Academy Medal on 2016. He has been listed in Highly Cited Researchers (Thomson Reuters) from 2014 to 2017.


ABSTRACT

Title: Regulatory mechanisms of innate immune responses

Innate immune cells sense pathogen invasion via pattern-recognition receptors (PRRs) such as Toll-like receptors (TLRs), RIG-I-like receptors (RLRs),NOD-like receptors (NLRs) and cGAS. The PRR signaling evoke immune responses by producing proinflammatory cytokines (Takeuchi and Akira. Cell 2010).Although inflammatory responses are critical for the clearance of pathogens, the uncontrolled innate immune cell activation can bring pathological consequences such as cytokine release syndrome and autoimmune diseases.Thus, the expression of cytokines is tightly controlled at the transcriptional and posttranscriptional mechanisms. The regulation of cytokine mRNA decayis found to be pivotal forresolving inflammation andpreventing autoimmune diseases. Regnase-1 is one of posttranscriptional immune regulators by acting as an RNase degrading immune-related mRNAs such as Il6 induced by PRR signaling in macrophages.Regnase-1 recognizes stem-loop structures in 3’ untranslated regions of cytokine mRNAs for degradation (Mino.Cell 2015). Regnase-1 is also critical for suppressing T cell activation and maintenance of immune homeostasis in mice. Furthermore, the Regnase-1 protein expression is controlled by IkB kinase (IKK)-mediated phosphorylation, and the mutations of these IKK phospho-sites are accumulated in the colons of ulcerative colitis patients (Kakiuchi. Nature 2020).These results demonstrate that RNA degradation by Regnase-1 is critical for the control of autoimmune diseases by targeting host inflammatory mRNAs. Recently, RNases are found not only to degrade self-mRNAs, but can degrade viral RNAs, and functions as the novel class of PRR. N4BP1 was identified as a novel RNase critical for the restriction of HIV-1 infection in T cells and macrophages by degrading viral mRNAs. Although the expression of N4BP1 is induced in response to type I IFN stimulation, T cells signaling resulted in the cleavage of N4BP1 by a MALT1 protease, which is potentially involved in the reactivation of HIV-1 latent cells (Yamasoba Nat Microbiol 2019). Collectively, RNA regulation is essential for the control of immune reactions to pathogen infection at the levels of direct control of foreign RNAs as well as the regulation of host inflammatory mRNAs.In this lecture, I will discuss the general mechanisms of innate immune sensing pathways, and their regulation mechanisms especially focusing on posttranscriptional controls.