Characterization of the anti-viral effects inhibited by the vaccinia virus K1 protein

vaccinia virus;protein kinase (PKR);NF-kappaB;K1 protein

Willis, Kristen L.

关键词: vaccinia virus;    protein kinase (PKR);    NF-kappaB;    K1 protein;   

Others  :  https://www.ideals.illinois.edu/bitstream/handle/2142/18499/Willis_Kristen.pdf?sequence=1&isAllowed=y

美国|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Vaccinia virus (VV), a member of the poxvirus family of double-stranded DNA viruses, is well-known as a highly effective vaccine against variola virus, the causative agent of smallpox.Poxviruses encode many strategies to evade the host immune and anti-viral response.One such host anti-viral response, activation of the double-stranded RNA activated protein kinase (PKR) pathway, is important in sensing the presence of intracellular viral genomes and their products.PKR is activated by dsRNA, a by-product of many virus infections, and exhibits its anti-viral effects in part via inhibition of protein synthesis and activation of the pro-inflammatory transcription factor NF-κB.I have identified the vaccinia virus K1 protein as an inhibitor of PKR activation.I determined that the C-terminal portion of the 2nd ankyrin repeat, a motif important for protein-protein interactions, is important for this inhibitory function.Further, K1 mediated PKR inhibition also blocks activation of downstream NF-κB in VV infected cells.Previous characterization of the K1 protein identified it as a host-range protein required for a productive infection.When the K1L gene is absent, replication is aborted due to shut-down in viral protein synthesis.I queried whether PKR was responsible for this effect.I found that replication when K1 was lacking could not be rescued by depletion of PKR protein levels.Hence K1 inhibition of PKR is not related to the host-range function.I next identified that the trigger for PKR activation is viral dsRNAs derived from early or intermediate viral transcription.As early dsRNAs have never been reported during a poxvirus infection, this finding was novel.Further, I found that there were higher levels of dsRNA present during a VV infection when K1 was absent or mutated.Finally, ectopic expression of K1 was able to inhibit PKR activation induced by viral dsRNAs.Together these data identifies a new function for the K1 protein and elucidates a strategy viruses utilize to inhibit detrimental host cell responses.