Model of the interplay between NS5A and PI4KIIIα.

A: Consensus sequence (red) of the PI4KIIIα interaction site (PFIS) derived from 672 NS5A sequences of all genotypes in the Los Alamos HCV database ( Green numbers in the top line refer to the degree of conservation (rounded). Numbers on the left and right refer to the positions of the flanking amino acids within NS5A. Variations from the consensus are listed according to their frequency. A proline found in the JFH-1 PFIS is marked in blue. Variants found only once are not shown. B: NS5A (light brown) interacts with PI4KIIIα (red). This interaction regulates NS5A phosphorylation status directly or indirectly. Active kinase promotes NS5A p56 formation, a fraction of which is hyperphosphorylated resulting in p58. P56 might positively influence viral RNA replication either directly or by affecting the morphology of the replication sites, for which additional host factors are probably required. PI4KIIIα interaction with NS5A and NS5B is required to trigger lipid kinase activity. This leads to formation of new PI4P pools, presumably involved in membranous web morphology.