M.D., Ph.D. Professor Kazuhiro Iwai
Cells consisting of our body must be maintained to be healthy. Deregulation of cellular function results in life-threating disorders, including cancer and neurodegenerative diseases. The aim of our research is to find out novel regulatory mechanisms of biological reactions and diseases. We are currently investigating signaling regulating NF-kB activation and cell death mediated by novel ubiquitin modification called linear ubiquitination, iron metabolism and iron-dependent cell death: ferroptosis in order to develop a new clinical therapy against chronic inflammatory disease and cancer.
Research and Education
We are conducting two research projects.
1) Functional analysis of the novel ubiquitin modification called linear ubiquitination, which is specifically generated by the LUBAC ubiquitin ligase. We found that the linear ubiquitin chain plays an important role in controlling inflammation, carcinogenesis, and immune response through activation of the transcription factor NF-kB and suppression of programmed cell death. It also shows that increased production or suppression of linear ubiquitin chains causes the development of lymphoma and autoinflammatory diseases. Based on our previous findings, we are currently conducting analysis of the role of linear ubiquitin chains in the onset and pathogenesis of cancer and immune disorders.
2) Cellular iron metabolism.
Iron is an essential trace metal that binds to proteins as iron ions or in the form of iron prosthetic groups called heme and iron-sulfur clusters, and functions for oxygen transport and ATP production. Recently, iron-induced cell death, ferroptosis is gaining attention due to its association with cancer and ischemic diseases. We are focusing on the mechanism of iron-induced ferroptosis, taking into account the relationship with aging and disorders. This laboratory is responsible for the education of physiology in Medical School. Many graduate students with various backgrounds conduct an individual research project under the supervision of faculty staffs.
- Kuno, S., Fujita, H., Tanaka, Y.-K., Ogra, Y. and Iwai, K. Iron-induced NCOA4 condensation regulates ferritin fate and iron homeostasis. EMBO Rep. 2022 Mar 23;e54278. doi: 10.15252/embr.202154278.
- Fuseya, Y., Fujita, H., Kim, M., Ohtake, F., Nishide, A., Sasaki, K., Saeki, Y., Tanaka, K., Takahashi, R. and Iwai, K. The HOIL-1L ligase modulates immune signaling and cell death via mono-ubiquitination of LUBAC. Nature Cell Biology. 22(6):663-673, 2020.
- Sasaki, K., Himeno, A., Nakagawa, T., Sasaki, Y., Kiyonari, H. and Iwai, K. Modulation of autoimmune pathogenesis by T cell-triggered inflammatory cell death. Nature Commun. 10(1):3878. doi:10.1038/s41467-019-11858-7.
- Fujita,, Tokunaga, A., Shimizu, S., Whiting, A. L., Aguilar-Alonso, F., Takagi, K., Walinda, E., Sasaki, Y., Shimokawa, T., Mizushima, T., Ohki, I., Ariyoshi, M., Tochio, H., Bernal, F., Shirakawa, M., and Iwai, K. Cooperative domain formation by homologous motifs in HOIL-1L and SHARPIN plays crucial roles in LUBAC stabilization. Cell Reports 23(4):1192-1204, 2018.
- Tokunaga F., Nakagawa T., Nakahara M., Saeki Y., Taniguchi M., Sataka S.-I., Tanaka K., Nakano H., Iwai K. Sharpin is a component of the NF-kB activating linear ubiquitin chain assembly complex. Nature. 471: 633-636, 2011.
Senior Lecturers：Izumi Yanatori
Assistant Professor：Hiroaki Fujita
Assistant Professor：Yasuhiro Fuseya