Furin-mediated protein processing in infectious diseases and cancer

Braun, Elisabeth; Sauter, Daniel

In contrast, H5 and H7 hemagglutinins of a large number of highly pathogenic avian influenza A viruses (HPAIV) can be cleaved by furin or PCSK5, which are present in many cell types. 56, 57 This is because they acquired a polybasic cleavage site upon insertion of additional lysine and/or arginine residues. Duplication of lysine and arginine residues in HA is facilitated by polymerase slippage as these amino acids are encoded by purine-rich codons. 58 Instead of the prototypical R-X-K/R-R↓ motif, some HPAIVs harbour a suboptimal K-X-K/R-R↓ cleavage motif. Proteolytic cleavage at this site is only efficient if additional positively charged amino acids upstream of this cleavage motif are present or if attachment sites for masking oligosaccharide chains are missing. 59, 60 Notably, a subset of H9N2 lowly pathogenic avian influenza A virus strains also harbour R-S-K-R↓ or R-S-R-R↓ sites that are not only cleaved by trypsin-like proteases, such as TMPRSS2 or HAT, but also by PCSKs. 61 However, their cleavage is only efficient in the presence of very high amounts of furin or upon mutation of a glycosylation site in HA. 62 Thus, the ability to exploit furin for efficient HA cleavage and the associated increase in pathogenicity are not only determined by the presence of a furin consensus target site, but also by adjacent residues and the absence of masking oligosaccharide chains.