IFITM3 Interacts with the HBV/HDV Receptor NTCP and Modulates Virus Entry and Infection

Viruses

Giuliano Ciarimboli¹  Felix Lehmann²  Christin Müller²  Dieter Glebe²  Nora Goldmann²  Lena Soppa²  John Ziebuhr²  Kira Alessandra Alicia Theresa Lowjaga³  Jörg Alber³  Massimo Palatini³  Silke Leiting³  Joachim Geyer³  Michael Kirstgen³  Simon Franz Müller³ 

[1] Experimental Nephrology, Medical Clinic D, Muenster University Hospital, 48149 Muenster, Germany;Institute of Medical Virology, National Reference Center for Hepatitis B Viruses and Hepatitis D Viruses, German Center for Infection Research (DZIF, Partner Site Giessen-Marburg-Langen), Justus Liebig University Giessen, 35392 Giessen, Germany;Institute of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Justus Liebig University Giessen, 35392 Giessen, Germany;

关键词: HBV;    HDV;    infection;    NTCP;    IFITM3;    virus entry;   

DOI  :  10.3390/v14040727

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown