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Appelman, M.D.* ; Nguyen, T.A.* ; Oswald, A. ; Lucko, A.M. ; Paulusma, C.C.* ; Protzer, U. ; van de Graaf, S.F.J.*

NTCP ubiquitination enables HBV infection.

JHEP Rep. 7:101534 (2025)

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BACKGROUND & AIMS: The sodium taurocholate cotransporting polypeptide (NTCP), the main hepatic uptake transporter of bile salts, is the docking receptor required for the HBV/HDV entry. However, the mechanism of NTCP-dependent internalization of HBV/HDV into hepatocytes is unclear. Thus, we investigated the contribution of post-translational modification of NTCP to transporter endocytosis and HBV infection. METHODS: NTCP ubiquitination was determined by immunoprecipitation of wild-type NTCP (NTCP^WT). Lysine (K) residues in the C terminus were substituted by arginine (R) to identify ubiquitination sites. HepG2 cells overexpressing NTCP mutants were analyzed for protein levels, bile salt uptake activity, NTCP endocytosis, and HBV infectivity. The global ubiquitination inhibitor TAK-243 was used to study effects on uptake and HBV infection in NTCP^WT-HepG2 and HepaRG cells. Sample sizes in the experiments were 3-10. RESULTS: NTCP was found to be ubiquitinated. Compared with NTCP^WT, the NTCP^K340R mutant showed reduced ubiquitination, indicating K340 as the main ubiquitination target. Furthermore, NTCP^K340R had increased membrane abundance, which coincided with enhanced bile salt uptake (28.2 ± 5.3 vs. 74.4 ± 5.8 pmol; p <0.0001). Compared with NTCP^WT, NTCP^K340R endocytosis was strongly impaired (100 ± 47 vs. 42 ± 19%; p = 0.0079), whereas HBV-derived myr-preS1 peptide binding was increased (100 ± 33 vs. 220 ± 98%; p <0.0001). Compared with NTCP^WT cells, HBV DNA content was strongly reduced in NTCP^K340R cells (52.74 ± 26.23 vs. 7.22 ± 3.28%; p = 0.0022). In line with this, TAK-243 reduced cellular ubiquitination levels and increased bile salt uptake (48.65 ± 2.27 vs. 105.8 ± 4.12 pmol; p = 0.0286), while reducing HBV DNA content in HepG2 (100 ± 44 vs. 18 ± 13%; p <0.0001) and HepaRG cells (100 ± 24 vs. 65 ± 6%; p = 0.0483). CONCLUSIONS: K340 is essential for NTCP ubiquitination. Inhibiting ubiquitination impaired NTCP endocytosis and reduced HBV infection, confirming that NTCP-mediated endocytosis is critical for HBV hepatic entry. IMPACT AND IMPLICATIONS: This study contributes to elucidating the process of how HBV enters hepatocytes, which is largely elusive. NTCP was found not only to be required for the binding of HBV to hepatocytes, but also to have a crucial role in hepatic internalization of HBV. In addition, a K at position 340 was identified as the main ubiquitination target of NTCP; ubiquitination-mediated endocytosis of NTCP at this position is likely to be the mechanism regulating HBV internalization. Thus, interfering with NTCP ubiquitination could provide a novel means to reduce HBV infection.

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