A Sialylated Voltage-Dependent Ca2+ Channel Binds Hemagglutinin and Mediates Influenza A Virus Entry into Mammalian Cells

  • Cell Host Microbe. 2018 Jun 13;23(6):809-818.e5. doi: 10.1016/j.chom.2018.04.015.
Yoichiro Fujioka  1 ,  Shinya Nishide  1 ,  Toyoyuki Ose  2 ,  Tadaki Suzuki  3 ,  Izumi Kato  4 ,  Hideo Fukuhara  4 ,  Mari Fujioka  1 ,  Kosui Horiuchi  1 ,  Aya O Satoh  1 ,  Prabha Nepal  1 ,  Sayaka Kashiwagi  1 ,  Jing Wang  1 ,  Mika Horiguchi  1 ,  Yuko Sato  3 ,  Sarad Paudel  1 ,  Asuka Nanbo  1 ,  Tadaaki Miyazaki  5 ,  Hideki Hasegawa  3 ,  Katsumi Maenaka  6 ,  Yusuke Ohba  7
Affiliations
  • 1. Department of Cell Physiology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan.
  • 2. Laboratory of Biomolecular Science, Faculty of Pharmaceutical Science, Hokkaido University, Sapporo 060-0812, Japan.
  • 3. Department of Pathology, National Institute of Infectious Diseases, Tokyo 162-0052, Japan.
  • 4. Center for Research and Education on Drug Discovery, Faculty of Pharmaceutical Science, Hokkaido University, Sapporo 060-0812, Japan.
  • 5. Department of Probiotics Immunology, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan.
  • 6. Laboratory of Biomolecular Science, Faculty of Pharmaceutical Science, Hokkaido University, Sapporo 060-0812, Japan; Center for Research and Education on Drug Discovery, Faculty of Pharmaceutical Science, Hokkaido University, Sapporo 060-0812, Japan.
  • 7. Department of Cell Physiology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan; Whitman Center, Marine Biological Laboratory, Woods Hole, MA 02543, USA. Electronic address: [email protected].
PMID: 29779930 DOI: 10.1016/j.chom.2018.04.015
Abstract

Influenza A virus (IAV) Infection is initiated by the attachment of the viral glycoprotein hemagglutinin (HA) to sialic acid on the host cell surface. However, the sialic acid-containing receptor crucial for IAV Infection has remained unidentified. Here, we show that HA binds to the voltage-dependent CA2+ channel CAv1.2 to trigger intracellular CA2+ oscillations and subsequent IAV entry and replication. IAV entry was inhibited by CA2+ channel blockers (CCBs) or by knockdown of CAv1.2. The CCB diltiazem also inhibited virus replication in vivo. Reintroduction of wild-type but not the glycosylation-deficient mutants of CAv1.2 restored CA2+ oscillations and virus Infection in CAv1.2-depleted cells, demonstrating the significance of CAv1.2 sialylation. Taken together, we identify CAv1.2 as a sialylated host cell surface receptor that binds HA and is critical for IAV entry.

Keywords
calcium channel; calcium channel blockers; calcium ion; hemagglutinin; influenza A virus; sialylation; virus entry; virus-host cell interaction.