Caspase cleavage of viral proteins, another way for viruses to make the best of apoptosis

Richard, A; Tulasne, D

Influenza viruses are structured into ribonucleoprotein segments consisting of viral RNA and viral proteins, the major one being the NP. Unlike avian NP, NP proteins from human influenza A and B viruses are long known to be caspase targets. 33, 34 Human influenza with uncleavable ('avian-like') NP is dramatically less lethal for mice, along with lower viral titers and faster clearance than its WT counterpart. This argues for the involvement of NP caspase cleavage in the virulence of influenza virus. But making avian NP cleavable (i.e. making the protein 'human-like' by introducing the same caspase cleavage site) does not enhance the viral virulence as could have been expected. Thus, modulating influenza pathogenicity through NP caspase cleavage would be a specificity of human strains that cannot be extrapolated to avian ones. 35 However, avian influenza pathogenicity might still be regulated by caspase cleavage. The viral ionic channel M2 protein is also cleaved by caspases, likely caspase 2 and/ or 3 36, 37 in both human and avian influenza viruses and was shown to be associated with avian influenza pathogenicity. 37 Altogether, these studies highlight that modulating influenza caspase sites attenuates the virus although through currently unknown mechanisms. 37, 38 Hepatitis C virus (HCV) often leads to chronic infection evolving to cirrhosis and possibly hepatocellular carcinoma. HCV core protein induces activation of caspases 2 and 6, and interacts with viral NS5A protein that is cleaved by the activated caspases. [39] [40] [41] [42] Several studies point to a role of NS5A cleavage in its subcellular localization. The protein is mainly found in the cytosol while exerting nuclear functions. NS5A caspase cleavage was first suggested to allow the removal of a C-terminal cytoplasmic retention signal along with the translocation of the C-terminal deleted NS5A to the nucleus, reminding what was already described for AMDV NS1 protein. 42 However, a study more recently reported a cytosolic localization of these C-terminal truncated forms of NS5A and no obvious role of NS5A caspase cleavage in its trafficking. 40 Although its characterization is well admitted, the functional relevance of NS5A cleavage is still debated.