Processing of Poly-ubiquitin in the Polyprotein of an RNA Virus

The RNA genome of several cytopathogenic (cp) strains of the pestivirus bovine viral diarrhea virus (BVDV) contains ubiquitin coding sequences (ucs). In noncytopathogenic BVDV strains, such insertions are missing. Gene expression of BVDV occurs via synthesis of a polyprotein which is subsequently processed by virus-encoded and cellular proteases. The insertion of ucs in the genomes of cpBVDV strains CP14 and Osloss leads to additional cleavages in the viral polyprotein. The respective processing events are mediated by cellular ubiquitin C-terminal hydrolases (UCHs). Release of monomeric ubiquitin (ubi) from the poly-ubi fragment encoded by CP14 is achieved by cleavage at the C-terminus as well as at the N-terminus of a complete ubi monomer. This result extends the current knowledge about poly-ubi processing. Processing of the polyprotein of CP14 and Osloss by UCHs generates an 80-kDa protein (p80), the marker protein of cpBVD viruses. Thus, the cp phenotype of both strains is apparently caused by the uptake of the ucs in the viral genome. Since cpBVDV strains arise in cattle in the course of a fatal disease, a direct linkage exists between the insertion of ucs and a lethal disease.