Identification of Caspase Cleavage Sites in KSHV Latency-Associated Nuclear Antigen and Their Effects on Caspase-Related Host Defense Responses

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Upon infecting a target cell, viruses must be able to overcome cellular defense responses to survive. Two of the most important cellular defense responses against viruses are apoptosis and the inflammasome, a component of the innate immune response. Apoptosis, a programmed cell death, functions to limit the spread of viruses by destroying the infected cell while innate immune responses control viral infections through other means. Both apoptosis and the inflammasome are mediated by caspases. However, many viruses are known to encode proteins that block, suppress or delay caspase activity following cellular infection in order to block cell death and interfere with the inflammasome. We show that LANA undergoes caspase-dependent cleavage in Kaposi’s sarcoma associated herpesvirus (KSHV)-infected cells, especially when exposed to oxidative stress. Through peptide, sequence and mutational analysis, we identified two sites for caspase cleavage in KSHV LANA, one in the N-terminal region and the other in the C-terminal region. Using synthetic peptides of these cleavage sites, we show that the C-terminal site can inhibit cleavage of poly (ADP-ribose) polymerase and enhance cellular survival. Furthermore, we demonstrate that this synthetic peptide inhibits the inflammasome response as evidenced by decreased interleukin-1beta (IL-1β) production. Mutation of these cleavage sites in LANA leads to a significant increase in the inflammasome response indicated by increased IL-1β production compared to wild-type LANA. Taken in total, these results provide evidence that these cleavage sites in LANA participate both in delaying apoptosis and blunting aspects of the innate immune response. These studies provide new insights into the mechanisms by which KSHV obviates the cellular defense responses that are activated following virus infection.

Vyšlo v časopise: Identification of Caspase Cleavage Sites in KSHV Latency-Associated Nuclear Antigen and Their Effects on Caspase-Related Host Defense Responses. PLoS Pathog 11(7): e32767. doi:10.1371/journal.ppat.1005064
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1005064

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