Kaposi sarcoma-associated herpesvirus (KSHV) is a human

Kaposi's sarcoma‐associated herpesvirus (KSHV) is a human gamma herpesvirus associated with several human malignancies. The replication and transcription activator (RTA) is required for KSHV lytic replication. TIR‐domain‐containing adaptor‐inducing beta interferon (TRIF) is an adaptor molecule critically involved in the Toll‐like receptor 3 (TLR‐3) and TLR‐4 signaling pathways for type I interferon (IFN) production, a key component of innate immunity. We find that RTA specifically degrades TRIF by shortening the half‐life of TRIF protein. This RTA‐mediated‐degradation is mediated through the ubiquitin‐proteasome pathway because proteasome inhibitors as well as knockdown of cellular ubiquitin expression alleviate the degradation. RTA may use its ubiquitin ligase domain and targets multiple regions of TRIF for the degradation. In addition, physiological levels of TRIF protein are down‐regulated during KSHV lytic replication when RTA is expressed. Finally, RTA down‐regulates double‐stranded RNA‐initiated activation of TLR‐3 pathway, in the absence of degradation of IFN regulatory factor 7 (IRF‐7). This work suggests that KSHV employs novel mechanism to block the innate immunity by degrading TRIF protein, which may contribute to evasion of host immunity by the virus.