RIKEN IMS AnnualReport 2020
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GαqGαiGαiGαq51Dendritic cellABStable immune synapseMHCTCRSMOCXCR4LFA-1HhHhHhPTCT cell activation1) Control of mRNA stability is one of the essential post-transcriptional mech-anisms to regulate gene expression levels. We have found that mRNA deadenyl-ase, an enzyme that triggers mRNA degradation by shortening the polyA tail, ensures normal development and function in tissues such as liver, adipocytes, pancreatic β-cells and T-cells (Figure A). The mRNA deadenylase targets dif-ferent mRNAs depending on the cell type and developmental stage. While the CCR4-NOT complex regulates the level of mRNAs encoding transcription fac-tors, cell cycle regulators and DNA damage response-related proteins in liver, the complex regulates progenitor cell markers and β cell-disallowed genes in pancreatic β-cells. When function of the CCR4-NOT complex is disrupted, those genes are abnormally increased, resulting in altered tissue function and disease phenotypes such as hepatitis and diabetes. These data suggest that the CCR4-NOT complex contributes to tissue homeostasis by modulating the transcriptome through mRNA deadenylation. We have been investigat-ing molecular mechanism by which the mRNA deadenylase recognizes target mRNAs depending on their context. The mRNA deadenylase also influences transcriptional activity of various genes. Our long-term goal is to understand how transcription and mRNA decay coordinate proper mRNA levels for tissue homeostasis.2) The morphogen Hedgehog (Hh) is responsible for patterning tissues dur-ing metazoan development. Hh pathway components localize to the immune synapse in a dynamic way and our results suggest involvement of Hedgehog in sustainable signaling at the immune synapse. We aim to understand how Hedgehog signaling at the immune synapse interacts with other T cell signaling pathways and how they are affected in cancer and autoimmunity (Figure B).Figure: Research projects in the laboratoryA. A role for mRNA deadenylation in tissue development and function.The CCR4-NOT complex promotes mRNA decay by short-ening the polyA tails of mRNAs. Reduction of unneces-sary mRNAs such as those encoding immature state- or cell death-related molecules ensures proper tissue development and function.B. Smoothened competes with CXCR4 for Gai coupling to fortify the immune synapse and regulate T cell activa-tion.The Hedgehog signaling pathway is active at the im-mune synapse between a naïve T call and a DC, where the signal transducer Smoothened (SMO) co-localizes with CXCR4 and forms heterodimers. SMO has a higher affinity for Gαi and, by depriving the available pool of Gαi proteins, it forces switching of CXCR4 signaling from Gαi to G9/11. This is the mechanism that allows naïve T cells to settle on the surface of a DC and become unresponsive to migratory cues, thus leading to the formation of a stable immune synapse.Recent Major PublicationsIto-Kureha T, Miyao T, Nishijima S, Suzuki T, Kozumi S-I, Villar-Brioness A, Takahashi A, Akinama N, Morita M, Nagura I, Ishikawa H, Ichijo H, Akinama T, Yamamoto T. The CCR4-NOT deadenylase complex safeguards thymic positive selection by down-regulating aberrant pro-apoptotic gene expression. Nat Commun 11, 6169 (2020)Mostafa D, Yanagiya A, Georgiadou E, Wu Y, Stylianides T, Rutter GA, Suzuki T, Yamamoto T. Loss of β-cell identity and diabetic phenotype in mice caused by disruption of CNOT3-dependent mRNA deadenylation. Commun Biol 3, 476 (2020)Takahashi A, Suzuki T, Soeda S, Takaoka S, Kobori S, Yamaguchi T, Mohamed H, Yanagiya A, Abe T, Shigeta M, Furuta Y, Kuba K, and Yamamoto T. The CCR4-NOT complex maintains liver homeostasis through mRNA deadenylation. Life Sci Alliance 3, e201900494 (2020)Invited presentationsYamamoto T. “The CCR4-NOT complex maintains liver homeostasis through mRNA deadenylation” The 43rd Annual Meeting of the Molecular Biology Society of Japan (Online) December 2020Laboratory for ImmunogeneticsTeam Leader: Tadashi Yamamoto

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