Abstract
Abstract Kaposi’s Sarcoma (KS) is an angioproliferative disease with symptoms including skin lesions that appear at different sites of the body caused by Kaposi’s Sarcoma Associated Herpesvirus (KSHV). The KSHV genome encodes genes pirated from the human genome that are homologous to cellular proteins that disrupt innate immune pathways. We have found a novel ORF in the KSHV genome that is homologous to the human IPS-1 protein. This viral IPS-1 proteins (vIPS-1) contains the PRO domain of IPS-1 but lacks the CARD and TM domains. We hypothesize that vIPS-1 is able to interact with the cellular TRAF3 protein. Western blot data shows that co-expression of vIPS-1 does not affect RIG-I, decreases the stability of human IPS-1 and TRIF, and increases the stability of TRAF3. Also, vIPS-1 interacts with TRAF3 via coimmunoprecipitation, and by co-expressing vIPS-1 with different TRAF3 mutants we found that vIPS-1 interacts with TRAF3 through the TRAF domain which is specifically required for TRAF3-mediated type I IFN production. Furthermore, our data shows that while expression of IPS-1 is able to inhibit VSV-GFP replication, expression of vIPS-1 significantly enhances the VSV-GFP replication, consistent with our hypothesis that vIPS-1 blocks the cellular immune responses. In conclusion, the KSHV vIPS-1 protein blocks antiviral immunity by interacting with TRAF3 leading to a decrease in antiviral activity.
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