title: Proteolytic disassembly of viral outer capsid proteins is crucial for reovirus-mediated type-I interferon induction in both reovirus-susceptible and reovirus-refractory tumor cells.
abstract: Oncolytic reovirus induces innate immune responses, which contribute to the antitumor activity of reovirus, following in vivo application. Reovirus-induced innate immune responses have been relatively well characterized in immune cells and mouse embryonic fibroblasts cells; however, the mechanisms and profiles of reovirus-induced innate immune responses in human tumor cells have not been well understood. In particular, differences in reovirus-induced innate immune responses between reovirus-susceptible and reovirus-refractory tumor cells remain unknown, although the intracellular trafficking of reovirus differs between these tumor cells. In this study, we examined reovirus-induced upregulation of interferon- (IFN-) β and of the proapoptotic gene, Noxa, in reovirus-susceptible and -refractory tumor cells. IFN-β and Noxa were significantly induced by reovirus via the IFN-β promoter stimulator-1 (IPS-1) signaling in both types of tumor cells. Inhibition of cathepsins B and L, which are important for disassembly of reovirus outer capsid proteins and escape into cytoplasm, largely suppressed reovirus-induced upregulation of IFN-β and Noxa expression in not only reovirus-susceptible but also reovirus-refractory tumor cells. These results indicated that in both reovirus-susceptible and reovirus-refractory tumor cells, disassembly of the outer capsid proteins by cathepsins and the escape into the cytoplasm were crucial steps for reovirus-induced innate immunity.
authors: Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Yuki
authors: Y
authors: Katayama
authors: Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Yuichi
authors: Y
authors: Terasawa
authors: Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Masashi
authors: 0000-0002-0376-508X
authors: M
authors: Tachibana
authors: Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan ; Laboratory of Hepatic Differentiation Research, National Institute of Biomedical Innovation, 7-6-8 Asagi, Saito, Ibaraki, Osaka 567-0085, Japan ; Center for Advanced Medical Engineering and Informatics, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan ; Laboratory of iPS Research, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Hiroyuki
authors: H
authors: Mizuguchi
authors: Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan ; Laboratory of Regulatory Sciences for Oligonucleotide Therapeutics, Clinical Drug Development Unit, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Fuminori
authors: F
authors: Sakurai
mesh_terms: D000818:Animals; D036022:Capsid Proteins / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D016899:Interferon-beta / Q000096:biosynthesis / Q000378:metabolism; D051379:Mice; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology / Q000821:virology; D050504:Oncolytic Viruses / Q000502:physiology*; D059748:Proteolysis; D012087:Reoviridae / Q000502:physiology*; D019065:Virus Assembly / Q000502:physiology*
chemical_list: D036022:Capsid Proteins; D016899:Interferon-beta