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  • Title: IFITM3 Interacts with the HBV/HDV Receptor NTCP and Modulates Virus Entry and Infection.
    Author: Palatini M, Müller SF, Kirstgen M, Leiting S, Lehmann F, Soppa L, Goldmann N, Müller C, Lowjaga KAAT, Alber J, Ciarimboli G, Ziebuhr J, Glebe D, Geyer J.
    Journal: Viruses; 2022 Mar 30; 14(4):. PubMed ID: 35458456.
    Abstract:
    The Na+/taurocholate co-transporting polypeptide (NTCP, gene symbol SLC10A1) is both a physiological bile acid transporter and the high-affinity hepatic receptor for the hepatitis B and D viruses (HBV/HDV). Virus entry via endocytosis of the virus/NTCP complex involves co-factors, but this process is not fully understood. As part of the innate immunity, interferon-induced transmembrane proteins (IFITM) 1-3 have been characterized as virus entry-restricting factors for many viruses. The present study identified IFITM3 as a novel protein-protein interaction (PPI) partner of NTCP based on membrane yeast-two hybrid and co-immunoprecipitation experiments. Surprisingly, IFITM3 knockdown significantly reduced in vitro HBV infection rates of NTCP-expressing HuH7 cells and primary human hepatocytes (PHHs). In addition, HuH7-NTCP cells showed significantly lower HDV infection rates, whereas infection with influenza A virus was increased. HBV-derived myr-preS1 peptide binding to HuH7-NTCP cells was intact even under IFITM3 knockdown, suggesting that IFITM3-mediated HBV/HDV infection enhancement occurs in a step subsequent to the viral attachment to NTCP. In conclusion, IFITM3 was identified as a novel NTCP co-factor that significantly affects in vitro infection with HBV and HDV in NTCP-expressing hepatoma cells and PHHs. While there is clear evidence for a direct PPI between IFITM3 and NTCP, the specific mechanism by which this PPI facilitates the infection process remains to be identified in future studies.
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