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

Richard, A; Tulasne, D

Kaposi sarcoma-associated herpesvirus (KSHV) establishes long-term infections leading to Kaposi sarcomas and can go through either latent or lytic cycle. When KSHV is reactivated, ORF57 (or Mta or KS-SM) is detected by western blot as a doublet, 30 with the smaller product being abolished by a pan caspase inhibitor. In vitro, caspase 7, which is activated on KSHV reactivation, and to a lesser extent caspases 5 and 10, are able to process ORF57 at 30 DETD 33 k. Interestingly, coexpression assays show that ORF57 cleavage product (i.e. ORF57 lacking residues 1-33) is no longer able to promote viral lytic gene expression. Accordingly, complementing a stable cell line containing an orf57-null KSHV genome with ectopic WT or uncleavable ORF57 promotes lytic gene expression, while ORF57 lacking residues 1-33 does not. Consistently, the number of cell-free virus particles dramatically increases when caspase 7 is inhibited. Thus, ORF57 cleavage would prevent proper expression of its downstream targets and subsequent full reactivation of KSHV, suggesting that it allows KSHV to maintain a persistent infection.