Suv4-20h2 protects against influenza virus infection by suppression of chromatin loop formation
Masami Shiimori,
Yu Ichida,
Ryota Nukiwa,
Toshie Sakuma,
Haruka Abe,
Rei Kajitani,
Yuji Fujino,
Akira Kikuchi,
Takeshi Kawamura,
Tatsuhiko Kodama,
Shinichi Toyooka,
Katsuhiko Shirahige,
Gunnar Schotta,
Keiji Kuba,
Takehiko Itoh,
Yumiko Imai
Affiliations
Masami Shiimori
Laboratory of Regulation for Intractable Infectious Diseases, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Osaka 567-0085, Japan
Yu Ichida
Laboratory of Regulation for Intractable Infectious Diseases, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Osaka 567-0085, Japan
Ryota Nukiwa
Laboratory of Regulation for Intractable Infectious Diseases, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Osaka 567-0085, Japan; Department of Anesthesiology and Intensive Care Medicine, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
Toshie Sakuma
Laboratory of Regulation for Intractable Infectious Diseases, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Osaka 567-0085, Japan
Haruka Abe
Laboratory of Regulation for Intractable Infectious Diseases, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Osaka 567-0085, Japan
Rei Kajitani
Department of Biological Information, School and Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Tokyo 152-8550, Japan
Yuji Fujino
Department of Anesthesiology and Intensive Care Medicine, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
Akira Kikuchi
Department of Molecular Biology and Biochemistry, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
Takeshi Kawamura
Laboratory for Systems Biology and Medicine, Research Center for Advanced Science and Technology, the University of Tokyo, Tokyo 153-8904, Japan; Proteomics Laboratory, Isotope Science Center, The University of Tokyo, Tokyo 113-0032, Japan
Tatsuhiko Kodama
Laboratory for Systems Biology and Medicine, Research Center for Advanced Science and Technology, the University of Tokyo, Tokyo 153-8904, Japan
Shinichi Toyooka
Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Okayama 700-8558, Japan
Katsuhiko Shirahige
Laboratory of Genome Structure and Function, Institute for Quantitative Biosciences, The University of Tokyo, Tokyo 113-0032, Japan
Gunnar Schotta
Department of Molecular Biology, Biomedical Center, Ludwig-Maximilians-University, 82152 Munich, Germany; Munich Center for Integrated Protein Science (CiPS), 81377 Munich, Germany
Keiji Kuba
Department of Biochemistry and Metabolic Science, Akita University Faculty of Medicine, Akita 010-8543, Japan
Takehiko Itoh
Department of Biological Information, School and Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Tokyo 152-8550, Japan
Yumiko Imai
Laboratory of Regulation for Intractable Infectious Diseases, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Osaka 567-0085, Japan; Laboratory for Infectious Systems, Institute for Protein Research, Osaka University, Osaka 565-0871, Japan; Corresponding author
Summary: The spatial organization of chromatin is known to be highly dynamic in response to environmental stress. However, it remains unknown how chromatin dynamics contributes to or modulates disease pathogenesis. Here, we show that upon influenza virus infection, the H4K20me3 methyltransferase Suv4-20h2 binds the viral protein NP, which results in the inactivation of Suv4-20h2 and the dissociation of cohesin from Suv4-20h2. Inactivation of Suv4-20h2 by viral infection or genetic deletion allows the formation of an active chromatin loop at the HoxC8-HoxC6 loci coincident with cohesin loading. HoxC8 and HoxC6 proteins in turn enhance viral replication by inhibiting the Wnt-β-catenin mediated interferon response. Importantly, loss of Suv4-20h2 augments the pathology of influenza infection in vivo. Thus, Suv4-20h2 acts as a safeguard against influenza virus infection by suppressing cohesin-mediated loop formation.
