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/S1P) plays a central role in Gn processing. Here we show that CCHFV-infected cells deficient in SKI-1/S1P 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/Gc or PreGn/PreGc) were secreted. Complementation of SKI-1/S1P-deficient cells with a SKI-1/S1P expression vector restored release of infectious virus (>10(6) PFU/ml), confirming that SKI-1/S1P processing is required for incorporation of viral glycoproteins. SKI-1/S1P may represent a promising antiviral target.
Bergeron
Eric
E
Special Pathogens Branch, Division of Viral and Rickettsial Diseases, National Center for Zoonotic, Vector-borne and Enteric Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA.
Vincent
Martin J
MJ
Nichol
Stuart T
ST
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D005816:Genetic Complementation Test; D006023:Glycoproteins / Q000378:metabolism*; D006056:Golgi Apparatus / Q000737:chemistry; D003225:Hemorrhagic Fever Virus, Crimean-Congo / Q000502:physiology*; D006801:Humans; D043484:Proprotein Convertases / Q000172:deficiency / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000502:physiology; D012697:Serine Endopeptidases / Q000172:deficiency / Q000378:metabolism*; D015678:Viral Structural Proteins / Q000378:metabolism*; D014771:Virion / Q000737:chemistry
D006023:Glycoproteins; D015678:Viral Structural Proteins; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; C115575:membrane-bound transcription factor peptidase, site 1