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

Richard, A; Tulasne, D

H-1 parvovirus (H-1PV) displays oncotropic and oncolytic features meaning it preferentially replicates in and kills transformed cells, mainly in a non-apoptotic manner. However H-1PV is able to activate caspases in non-transformed cells, leading to the cleavage of NS1, a non-structural protein (NS) notably involved in viral DNA replication and gene expression by transactivating P38 promoter, which controls the synthesis of capsid proteins. Cleaved NS1 protein (named NS1-Nterm) lacks its C-terminal transactivation domain. When ectopically expressed, NS1-Nterm acts as a dominant negative on NS1-driven P38 promoter transactivation, and dramatically decreases viral production. Moreover, a molecular clone expressing an uncleavable version of NS1 tends to generate more virions. As cancer cells are often refractory to proper apoptotic induction, we propose that H-1PV oncotropism is due, at least in part, to the inability of cancer cells to cleave NS1 protein, thus allowing strong virus production. On the other hand, NS1 cleavage would act as a sensor of antiviral defenses and accordingly attenuate viral amplification, likely to favor persistent infection (our unpublished results). Crimean-Congo hemorrhagic fever virus (CCHFV) causes severe coagulation dysfunction in humans. CCHFV nucleocapsid protein (NP) is an important structural protein also involved in viral replication and, when ectopically expressed with an apoptotic factor such as Bax protein, it generates two fragments through cleavage at a consensual 266 DEVD 269 k motif. 32 A caspase 3 inhibitor and cells lacking caspase 3 both allows a one log-increase in the production of virions, which suggests that caspase activation is involved in CCHFV attenuation. Thus, NP caspase cleavage and/or NP-related products may participate to this attenuation although the mechanisms remain to be investigated. Interestingly, the caspase cleavage site is conserved within all the strains that were checked, suggesting that it is an important feature for CCHFV regulation.