Subtilisin-like proprotein convertases (SPCs); host enzymes controlled viral protein processing and maturation

Abstract

The cellular subtilisin-like proprotein convertases (SPCs) are responsible for virion maturation process which occurs in secretory vesicles, primes virion maturation and viral infectivity. Eight SPCs, SPC1 (furin/PACE), SPC2 (PC2), SPC3 (PC1/PC3), SPC4 (PACE4), SPC5 (PC4), SPC6 (PC5/PC6A) and SPC7 (LPC/PC7/PC8) and PCSK9, were identified. The consensus substrate sequence is -RX(K/R)R▼X- (X can be any amino acid, ▼ represents the cleavage site). The conformational change of viral proteins can be triggered by a low pH in the endosomes, as in the case of influenza virus, or by the interaction with a secondary receptor protein at the cell surface, as the case of HIV. In flaviviruses, the functional roles of charged residues locate to the SPC consensus sequence in cleavage site of prM protein and provide cleavability affect to virus replication. Changes in the prM-cleavage level were associated with altered proportions of extracellular virions and subviral particles. The hemagglutinin (HA) protein is a critical determinant of the pathogenicity of avian influenza viruses, with a clear link between HA cleavability and virulence. The highly pathogenic avian influenza virus, in which contain high numbers of basic amino acid sequence at the HA cleavage site, can be converted to low numbers of basic amino acid sequence of a typical avirulent virus. The processing by SPCs is an important control mechanism for the biological activity of viral surface proteins. The molecular mechanisms underlying the recognition of SPCs by viral glycoproteins were described, including recent findings demonstrating differential SPC-recognition of viral and cellular substrates. Proteolytic activation of envelope glycoproteins is necessary for entry of viruses into the host cell and, hence, for their ability to undergo multiple replication cycles. Proteolytic cleavage is the first step in the activation of virus fusion proteins and is followed by a conformational change resulting in the exposure of the fusion domain. The conformational change can be triggered by a low pH in the endosomes, or by the interaction with a secondary receptor protein at the cell surface.