IRF7, a members of the IFN regulatory family, when activated by viral infection or by toll-like receptor stimulation induces type I IFN transcription in many cell types, including DCs. We showed that IRF7 is conjugated to SUMO 1, 2 and 3. The SUMO modifications of IRF7 were caused by pathogen mediated activation of TLR and RIG-I pathways, causing strong inhibition of IFN transcription. Similarly, a related factor IRF3 was found SUMOylated causing similar inhibition of IFN transcription. It is likely that this SUMO modification is a mechanism to attenuate IFN induction postactivation to control excessive inflammation. Furthermore, we found that the Ebola virus VP35 strongly inhibits IFN induction in DCs by prematurely SUMOylating IRF7 and IRF3. Our analysis showed that VP35 directly interacts with IRF7 as well as the components of host SUMO modification machinery including SUMO E3 ligase PIAS1 and the E2 enzyme Ubc9. In accordance, down regulation of PIAS1 by small hairpin RNA partially alleviated VP35 repression of IFN induction.

Project Start
Project End
Budget Start
Budget End
Support Year
23
Fiscal Year
2009
Total Cost
$760,460
Indirect Cost
City
State
Country
Zip Code
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