RRC ID 67650
Author Iwamoto M, Saso W, Sugiyama R, Ishii K, Ohki M, Nagamori S, Suzuki R, Aizaki H, Ryo A, Yun JH, Park SY, Ohtani N, Muramatsu M, Iwami S, Tanaka Y, Sureau C, Wakita T, Watashi K.
Title Epidermal growth factor receptor is a host-entry cofactor triggering hepatitis B virus internalization.
Journal Proc Natl Acad Sci U S A
Abstract Sodium taurocholate cotransporting polypeptide (NTCP) is a host cell receptor required for hepatitis B virus (HBV) entry. However, the susceptibility of NTCP-expressing cells to HBV is diverse depending on the culture condition. Stimulation with epidermal growth factor (EGF) was found to potentiate cell susceptibility to HBV infection. Here, we show that EGF receptor (EGFR) plays a critical role in HBV virion internalization. In EGFR-knockdown cells, HBV or its preS1-specific fluorescence peptide attached to the cell surface, but its internalization was attenuated. PreS1 internalization and HBV infection could be rescued by complementation with functional EGFR. Interestingly, the HBV/preS1-NTCP complex at the cell surface was internalized concomitant with the endocytotic relocalization of EGFR. Molecular interaction between NTCP and EGFR was documented by immunoprecipitation assay. Upon dissociation from functional EGFR, NTCP no longer functioned to support viral infection, as demonstrated by either (i) the introduction of NTCP point mutation that disrupted its interaction with EGFR, (ii) the detrimental effect of decoy peptide interrupting the NTCP-EGFR interaction, or (iii) the pharmacological inactivation of EGFR. Together, these data support the crucial role of EGFR in mediating HBV-NTCP internalization into susceptible cells. EGFR thus provides a yet unidentified missing link from the cell-surface HBV-NTCP attachment to the viral invasion beyond the host cell membrane.
Volume 116(17)
Pages 8487-8492
Published 2019-4-23
DOI 10.1073/pnas.1811064116
PII 1811064116
PMID 30952782
PMC PMC6486715
MeSH ErbB Receptors / genetics ErbB Receptors / metabolism Hep G2 Cells Hepatitis B virus* / pathogenicity Hepatitis B virus* / physiology Host-Pathogen Interactions / genetics Host-Pathogen Interactions / physiology Humans Organic Anion Transporters, Sodium-Dependent* / genetics Organic Anion Transporters, Sodium-Dependent* / metabolism Symporters* / genetics Symporters* / metabolism Virus Internalization*
IF 9.412
DNA material pCAG-HIVgp (RDB04394) pCMV-VSV-G-RSV-Rev (RDB04393)