Figure 5.

Proposed mechanism: HCV increases the abundance of desmosterol in replication membranes through NS3-4A–mediated proteolysis of DHCR24. A, sequence alignment of other known NS3-4A protein substrates with DHCR24 reveals previously unnoticed sequence similarity. B, during HCV replication, NS3-4A located on the ER membrane interacts with DHCR24 and cleaves it at the peptide bond between Cys⁹¹ and Thr⁹². This inactivates the enzyme and/or leads to its diffusion away from the membrane. The result is decreased conversion of desmosterol to cholesterol in the membrane where NS3-4A resides and where RNA replication occurs. This is associated with increased membrane diffusivity and RNA replication. HCV sequences are from HCV-J6 (genotype 2a).