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

Richard, A; Tulasne, D

Parvovirus Aleutian mink disease virus (AMDV) can lead, at a single cell level, to either permissive infection, namely high levels of both viral DNA replication and production of viruses, or persistent infection with low viral DNA replication and almost no production of progeny virions. On permissive infection, AMDV induces caspase activation that is necessary for viral amplification. 22 This requirement was associated with NS1 protein being cleaved through two caspase 3 sites leading to five NS1-related products. 23 When one site is mutated within AMDV molecular clones, the viral production is strongly reduced and even aborted when both sites are disrupted. Interestingly, wild-type (WT) NS1 protein, which exerts replicative and transcriptional functions, is mostly nuclear, but when one of its cleavage sites is disrupted, the protein remains cytosolic resulting in a dramatic decrease in NS1-dependent viral protein (VP) expression. NS1-related C-terminal products, also nuclear, are suggested to be actively Human papillomavirus (HPV) is mostly known to infect epithelial cells of the genital tract and cause cervical cancers. On epithelial differentiation, HPV induces a DNA damage response that leads to caspase 3-dependent apoptosis. 24 Interestingly, HPV E1, a protein involved in viral DNA replication, is a target for caspases 3 and 7 at a site that is conserved in all genital HPVs and preventing E1 cleavage reduces viral amplification. When compared with chemically induced apoptosis, HPV-induced apoptotic markers are limited. Interestingly, HPV increases the levels of both antiapoptotic Bcl2 and Survivin proteins. 25 HPV pro-and antiapoptotic properties might achieve a caspase activity threshold that is sufficient for E1 cleavage and viral amplification, but not lethal for the host cell. Besides E1, HPV E6 protein is cleaved by caspases as well, but the functional consequences remain unknown. 26 Human astroviruses (HAstV) are responsible for gastroenteritis. In Yuc8 strain, orf2 encodes the precursor of viral capsid proteins, VP90, whose processing yields VP70. Besides, HAstV activates caspases 3, 4, 6, 7, 8 and 9. 27, 28 In vitro, caspases 3, 8 and 9 are able to target VP90 27 but only caspase 3 or 9 silencing reduces VP70 generation on infection. Interestingly, both intracellular VP90 processing into VP70 and progeny virion release are lost in the presence of a pan caspase inhibitor. However, in opposition to what was first suggested, viral release needs caspase activation but does not need VP90 processing into VP70 to be achieved. 27 But yielding fully infectious viruses does require shorter polypeptides to be created through VP70 further processing by trypsin. Thus, first cleaving VP90 to generate VP70 likely represents a crucial intermediate event during HAstV infection.