Sumoylation at the Host-Pathogen Interface

Wilson, Van G.

In contrast to the HPV 16E6 protein, the Ebola VP35 protein stimulates the ligase activity of its target, PIAS1. PIAS1 is an endogenous SUMO ligase for IRF7. Sumoylation of IRF7 decreases its transcriptional activity on the interferon β promoter and may be part of a normal feedback process to attenuate the interferon response and limit inflammation. In co-immunoprecipitations VP35 was found complexed to both PIAS1 and IRF7, and VP35 expression led to enhanced sumoylation of IRF7 that reduced its transcriptional activity. When co-expressed with a PIAS1 inactive mutant VP35 was unable to enhance sumoylation of IRF7, indicating that the VP35 effect on IRF7 is mediated through PIAS1 alone. Normally IRF7 is sumoylated at lysine 406, but VP35 induced sumoylation at multiple lysines, even in a lysine 406 mutant, suggesting that VP35 is causing promiscuous sumoylation of this target to ensure its transcriptional repression. Similar effects were seen with IRF3. Consequently, it appears that Ebola is using VP35 to down regulate the innate immune response by hypersumoylating two transcription factors involved in interferon induction to reduce their transactivation capacity and decrease interferon production.