Figure 2. Host factors that have been identified by CRISPR–Cas screens as important for infection and replication of viruses in the family Flaviviridae.

The flaviviruses Zika virus (ZIKV), dengue virus (DENV) and West Nile virus (WNV) enter the cell by attachment to cell surface molecules, including heparan sulfate proteoglycans (HSPG) and potentially other protein receptors^61,71,77. After uncoating, viral (+)RNA is translated by host ribosomes. The ribosomal subunit 40S ribosomal protein S25 (RPS25) is important for DENV infection and for translation of hepatitis C virus (HCV) RNA, but is dispensable for host mRNA translation^61,158. The flavivirus polyprotein is inserted into the endoplasmic reticulum (ER) membrane and cleaved by viral and host proteases, including the host signal peptidase complex⁷⁰. The viral proteins assemble a replication complex in close association with several ER-resident host protein complexes: the oligosaccharyltransferase (OST) complex, the translocon-associated protein (TRAP) complex and components of the ER-associated protein degradation (ERAD) pathway^61,69,70,71. Notably, different flaviviruses have different dependencies on the two distinct OST multiprotein complexes, which contain either an STT3A or an STT3B catalytic subunit. The ERAD-related host factors belong to the classical ERAD complex and the ER membrane protein complex (EMC). HCV enters hepatocytes through the receptors CD81, occludin (OCLN) and claudin 1 (CLDN1)^61,159, and the host microRNA miR-122 binds to and stabilizes the 5′ UTR of the HCV RNA^61,160. FAD biosynthesis, catalysed by riboflavin kinase (RFK) and FAD synthase (FLAD1), is important for HCV RNA synthesis⁶¹. ELAVL1 binds to the 3′ UTR of HCV to circularize the viral genome by interacting with La protein (also known as SSB) and displacing polypyrimidine-tract-binding protein 1 (PTB) to stimulate virus replication^61,161. Cyclophilin A (CYPA) is required for HCV replication through its interaction with NS5A^61,83. UBE2J1, ubiquitin-conjugating enzyme E2 J1; YFV, yellow fever virus.

PowerPoint slide