Taisei Hirouchi
Bibliography
2015 Graduated with a degree in Pharmaceutical Science, Faculty of Pharmaceutical Science, Osaka University (Prof. Hitoshi Hashimoto) 2017 M.S. Graduate School of Frontier Sciences, The University of Tokyo (Prof. Sumio Sugano) 2017-2019 Junior Research Associate Program. Laboratory for Developmental Neurobiology, Center for Brain Science, RIKEN (Dr. Katsuhiko Mikoshiba) 2020-2022 Research Fellowship for Young Scientists (DC2, Japan Society for the Promotion of Science (JSPS)). Laboratory of Tumor Cell Biology, Graduate School of Frontier Sciences, The University of Tokyo (Prof. Kaoru Uchimaru) 2022 Ph.D. Graduate School of Frontier Sciences, The University of Tokyo (Prof. Kaoru Uchimaru) 2022-present Post-doc. Dept. Pharmacology, Graduate School of Medicine, Kyoto University (Prof. Yasunori Hayashi)
Research topics
Unbiased compound screening with a reporter gene assay highlights the role of p13 in the cardiac cellular stress response
We recently showed that a 13-kDa protein (p13), the homolog protein of formation of mitochondrial complex V assembly factor 1 in yeast, acts as a potential protective factor in pancreatic islets under diabetes. Here, we aimed to identify known compounds regulating p13 mRNA expression to obtain therapeutic insight into the cellular stress response. A luciferase reporter system was developed using the putative promoter region of the human p13 gene. Overexpression of peroxisome proliferator-activated receptor gamma coactivator 1α, a master player regulating mitochondrial metabolism, increased both reporter activity and p13 expression. Following unbiased screening with 2320 known compounds in HeLa cells, 12 pharmacological agents (including 8 cardiotonics and 2 anthracyclines) that elicited >2-fold changes in p13 mRNA expression were identified. Among them, four cardiac glycosides decreased p13 expression and concomitantly elevated cellular oxidative stress. Additional database analyses showed highest p13 expression in heart, with typically decreased expression in cardiac disease. Accordingly, our results illustrate the usefulness of unbiased compound screening as a method for identifying novel functional roles of unfamiliar genes. Our findings also highlight the importance of p13 in the cellular stress response in heart[1].
A novel missense mutation in the IP3R1 suppressor domain causes spinocerebellar ataxia type 29
Type 1 inositol trisphosphate receptor (IP3R1) is an intracellular IP3-induced Ca2+ release channel and is recently identified as a causative gene of spinocerebellar ataxia type 15/16 (SCA15/16; MIM #606658) and type 29 (SCA29; MIM #117360). While several studies have reported the effect of SCA15/16-associated mutations, there have been no reports how SCA29-associated mutations affect IP3R1 functions. To reveal the mechanism by which the SCA29-associated mutation contributes to SCA29, I investigated the effect of a novel SCA29-associated missense mutation in the IP3R1 suppressor domain, Arg36Cys, on IP3R1 channel properties. Here, I reported that Arg36Cys mutation significantly increased binding affinity for IP3 to the NH2-terminal region of human IP3R1. Moreover, I also found that cells expressing Arg36Cys variant drastically changed the property of intracellular Ca2+ signal from a transient to a sigmoidal pattern. These results demonstrated that the Arg36Cys mutation influences both the IP3 binding affinity and the Ca2+ release properties of IP3R1. My study provides a novel insight that abnormal intracellular Ca2+ signals may underlie SCA29, which is an initial step towards a better understanding of the pathogenesis of SCA29[2].
Analysis for the voltage-gated Ca2+ channel ectopically expressed in adult T-cell leukemia (ATL) cases
Adult T-cell leukemia-lymphoma (ATL) is an aggressive T-cell malignancy caused by human T-cell leukemia virus type 1 (HTLV-1). It has been reported that T-cell receptor (TCR) pathway is recurrently mutated in ATL. Ca2+ is a central modulator downstream of TCR. However, regulatory mechanism of the cytoplasmic Ca2+ signals in ATL is still unclear. Through the detailed expression profiling of the Ca2+ transport genes, we found Ca2+ channel “Cav3.2” was ectopically expressed in aggressive ATL cases. We analyzed whether Cav3.2 ectopic expression affects intracellular Ca2+ homeostasis and Ca2+ signaling (unpublished Data).
FAM81A, a major postsynaptic protein, regulates the condensation of postsynaptic proteins via liquid-liquid phase separation
FAM81A is a postsynaptic density (PSD) localized protein. It seems to be one of the most major postsynaptic proteins because it was recurrently detected in the PSD proteome datasets in mammals. However, its functions or characteristics are still unclear. We have recently demonstrated that recombinant mouse Fam81a undergoes liquid-liquid phase separation, interacts with PSD proteins, including PSD-95, SynGAP, and NMDA receptors, and promotes condensation of those proteins. Our results characterize FAM81A as a novel synaptic protein facilitating the assembly of proteins within PSD[3].
Publications and preprints
- ↑
Inoue, N., Hirouchi, T., Kasai, A., Higashi, S., Hiraki, N., Tanaka, S., Nakazawa, T., Nunomura, K., Lin, B., Omori, A., Hayata-Takano, A., Kim, Y.J., Doi, T., Baba, A., Hashimoto, H., & Shintani, N. (2018).
Unbiased compound screening with a reporter gene assay highlights the role of p13 in the cardiac cellular stress response. Biochemical and biophysical research communications, 495(2), 1992-1997. [PubMed:29180011] [WorldCat] [DOI] - ↑
Casey, J.P., Hirouchi, T., Hisatsune, C., Lynch, B., Murphy, R., Dunne, A.M., Miyamoto, A., Ennis, S., van der Spek, N., O'Hici, B., Mikoshiba, K., & Lynch, S.A. (2017).
A novel gain-of-function mutation in the ITPR1 suppressor domain causes spinocerebellar ataxia with altered Ca2+ signal patterns. Journal of neurology, 264(7), 1444-1453. [PubMed:28620721] [WorldCat] [DOI] - ↑ Kaizuka T, Hirouchi T, Saneyoshi T, Hayashi Y, Takumi T. (2023)
DRACC1, a major postsynaptic protein, regulates the condensation of postsynaptic proteins via liquid-liquid phase separation. bioRxiv.
Academic Society
- The Japanese Society for Neuroscience
- The Japanese Society for Neurochemistry
- The Japanese Society of HTLV-1 and Associated Diseases
Contact address
Konoe-cho, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
Room 404, Building A, Department of pharmacology, Graduate School of Medicine, Kyoto University
E-mail address: hirouchi.taisei.3c@kyoto-u.ac.jp
Tel: 075-753-4393 (ext. 84635)