Our laboratory seeks a better understanding of the molecular mechanisms of innate immunity. The innate immune system is a first line of defense against viral infection. Pattern recognition receptors (PRRs) recognize pathogen-associated molecular patterns (PAMPs) and trigger innate immune signaling. Toll-like receptors 3 (TLR3) is a PRRs and recognizes viral double-stranded RNA in endosome. We have previously isolated TICAM-1, which is a solo adaptor of TLR3 (Oshiumi et al., 2003) . The adaptor protein activates IRF-3 and NF-κB transcription factors, thereby inducing the production of type I interferon and pro-inflammatory cytokine. The TLR3-TICAM-1 pathway plays a crucial role during poliovirus infection. Conventional dendritic cells require TLR3 and TICAM-1 to produce type I interferon in response to poliovirus infection. Thus, TICAM-1 knockout mice are highly susceptibly to poliovirus infection (Oshiumi et al., 2011) . The TLR3-TICAM-1 pathway is also important for type I and type III interferon production in response to exosomes released from HCV-infected hepatocytes (Okamoto et al., 2014) .
Cytoplasmic viral double-stranded RNA is recognized by RIG-I-like receptors, which includes RIG-I and MDA5. We have identified several factors involved in RLRs activation. The Riplet ubiquitin ligase was isolated by yeas two-hybrid screening to isolate the protein bound to RIG-I. The protein mediates K63-linked polyubiquitination of the RIG-I C-terminal region, leading to TRIM25-mediated RIG-I activation (Oshiumi et al., 2009; Oshiumi et al., 2012; Oshiumi et al., 2013). Riplet knockout mice are susceptible to vesicular stomatitis virus infection, suggesting the importance of Riplet-mediated C-terminal polyubiquitination in antiviral innate immune response (Oshiumi et al., 2010) . RIOK3 is a protein kinase associates with MDA5. RIOK3 phosphorylates RIOK3 C-terminal region, which results in inhibition of MDA5 assembly along viral double-stranded RNA required for triggering the signal (Takashima et al., 2015).
We have made several important discoveries as described above, and now we are studying about antiviral innate immune response, anti-tumor immune response, and class-switch recombination in B cells.
Kouwaki T, Okamoto M, Tsukamoto H, Fukushima Y, Matsumoto M, Seya T, Oshiumi H.
Zyxin stabilizes RIG-I and MAVS interactions and promotes type I interferon response. Scientific Reports 7: 11905, 2017
Kouwaki T, Fukushima Y, Daito T, Sanada T, Yamamoto N, Mifsud EJ, Leong CR, Tsukiyama-Kohara K, Kohara M, Matsumoto M, Seya T, and Oshiumi H. Extracellular vesicles including exosomes regulate innate immune response to hepatitis B virus infection. Frontiers in Immunology 7: 335 eCollection 2016
Okamoto, M., Oshiumi, H., Azuma, M., Kato, N., Matsumoto, M., and Seya, T. (2014). IPS-1 is essential for type III IFN production by hepatocytes and dendritic cells in response to hepatitis C virus infection. Journal of immunology 192, 2770-2777.
Oshiumi, H., Matsumoto, M., Funami, K., Akazawa, T., and Seya, T. (2003). TICAM-1, an adaptor molecule that participates in Toll-like receptor 3-mediated interferon-beta induction. Nature immunology 4, 161-167.
Oshiumi, H., Matsumoto, M., Hatakeyama, S., and Seya, T. (2009). Riplet/RNF135, a RING finger protein, ubiquitinates RIG-I to promote interferon-beta induction during the early phase of viral infection. The Journal of biological chemistry 284, 807-817.
Oshiumi, H., Matsumoto, M., and Seya, T. (2012). Ubiquitin-mediated modulation of the cytoplasmic viral RNA sensor RIG-I. Journal of biochemistry 151, 5-11.
Oshiumi, H., Miyashita, M., Inoue, N., Okabe, M., Matsumoto, M., and Seya, T. (2010). The ubiquitin ligase Riplet is essential for RIG-I-dependent innate immune responses to RNA virus infection. Cell host & microbe 8, 496-509.
Oshiumi, H., Miyashita, M., Matsumoto, M., and Seya, T. (2013). A distinct role of Riplet-mediated K63-Linked polyubiquitination of the RIG-I repressor domain in human antiviral innate immune responses. PLoS pathogens 9, e1003533.
Oshiumi, H., Okamoto, M., Fujii, K., Kawanishi, T., Matsumoto, M., Koike, S., and Seya, T. (2011). The TLR3/TICAM-1 pathway is mandatory for innate immune responses to poliovirus infection. Journal of immunology 187, 5320-5327.
Takashima, K., Oshiumi, H., Takaki, H., Matsumoto, M., and Seya, T. (2015). RIOK3-Mediated Phosphorylation of MDA5 Interferes with Its Assembly and Attenuates the Innate Immune Response. Cell reports 11, 192-200.
Student interesting in studying in our laboratory should apply to Graduate School of Medical Sciences at Kumamoto University.
TEL : 096-373-5135（研究室）
Department of Immunology,
Graduate School of Medical Sciences,
Faculty of Life Sciences,
School of Medicine
1-1-1, Honjo, Chuo-ku, Kumamoto, 860-8556 Japan