Internally located signal peptides direct hepatitis C virus polyprotein processing in the ER membrane

An endoplasmic reticulum (ER) signal peptide is an amino acid sequence motif that directs the translocation of nascent polypeptides to the lumen of ER membrane. Most of known ER signal peptides are either N-terminal cleavable or internally uncleavable. In the structural protein region of hepatitis C virus (HCV) polyprotein, however, four internally located cleavable signal peptides are arranged in a tandem array. The published experimental results indicated that the nascent HCV polyprotein is processed in the ER membrane by host signal peptidase(s) to the respective viral proteins. Here we propose that the four ER signal peptides lead the nascent HCV polyprotein to ER membrane, and the four internally located cleavable signal peptides are the sole determinant for the compartment localization of the matured viral proteins. After cleavage at the C-terminus, the signal peptides retain at the C-terminus of mature proteins, and serve as ER membrane anchors. The signal peptide directed polyprotein processing in the ER membrane preludes the virion assembly and budding from the ER membrane. This unique processing may be a general mechanism adopted by many types of virus for virion assembly and replication. The revelation of signal peptidase involved in HCV polyprotein processing presents a novel drug target to suppress HCV viral replication for the much needed HCV therapy.