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: yohba@med.hokudai.ac.jp.

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 CA_v1.2 to trigger intracellular CA²⁺ oscillations and subsequent IAV entry and replication. IAV entry was inhibited by CA²⁺ channel blockers (CCBs) or by knockdown of CA_v1.2. The CCB diltiazem also inhibited virus replication in vivo. Reintroduction of wild-type but not the glycosylation-deficient mutants of CA_v1.2 restored CA²⁺ oscillations and virus Infection in CA_v1.2-depleted cells, demonstrating the significance of CA_v1.2 sialylation. Taken together, we identify CA_v1.2 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.

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