Scavenger receptor class F member 2 is an intracellular receptor for hepatitis B virus

Hepatitis B virus (HBV) infects hepatocytes by specific binding to the cell-surface receptor-sodium taurocholate cotransporting polypeptide (NTCP)-through the preS1 region of its large envelope protein, followed by a less well-understood transport process across the cytoplasm to the nucleus. Here, we report that scavenger receptor class F member 2 (SCARF2), a single-pass transmembrane protein, functions as an intracellular receptor for HBV. SCARF2 binds to a preS1 region downstream of the NTCP binding site through its N-terminal epidermal growth factor (EGF)-like domains 4-6, and its proline-rich C-terminal domain also plays an indispensable role in the infection. The internalized HBV virions are transported to the cytoplasmic side of nuclear pore complexes within the SCARF2-containing endosomes. HBV nucleocapsid release from the endosomal vesicles is impaired by knockdown of SCARF2. These results suggest a model in which SCARF2 conveys HBV to the periphery of nuclear pore complexes (NPCs) and ultimately leads to viral nucleocapsid release for nuclear entry.