Crimean-Congo hemorrhagic fever virus glycoprotein processing by the endoprotease SKI-1/S1P is critical for virus infectivity

Crimean-Congo hemorrhagic fever virus (CCHFV) causes severe human disease. The CCHFV medium RNA encodes a polyprotein which is proteolytically processed to yield the glycoprotein precursors PreGn and PreGc, followed by structural glycoproteins Gn and Gc. Subtilisin kexin isozyme-1/site-1 protease (SKI-1/SIP) plays a central role in Gn processing. Here we show that CCHFV-infected cells deficient in SKI-1/SIP produce no infectious virus, although PreGn and PreGc accumulated normally in the Golgi apparatus, the site of virus assembly. Only nucleoprotein-containing particles which lacked virus glycoproteins (Gn/Ge or PreGn/PreGc) were secreted. Complementation of SKI-1/SlP-deficient cells with a SKI-1/SIP expression vector restored release of infectious virus (> 10(6) PFU/ml), confirming that SKI-1/SIP processing is required for incorporation of viral glycoproteins. SKI-1/SIP may represent a promising antiviral target.