Roles Of WDR5 In Assembly Of The VISA-associated Complex And Cellular Antiviral Response

Viral infection could be detected by the pattern recognition receptors of the innate immune system, leading to activation of signaling transduction, results in activation of the transcription factors NF-κB and IRF3. These transcription factors collaborate to induce typeⅠinterferons (IFNs). TypeⅠinterferons further induce expression of the Anti-Viral Proteins. AVPs inhibit viral replication as well as induce the apoptosis of infected cells, therefore mediate cellular antiviral response. It is well admitted that the typeⅠinterferons play a very important role in antiviral immunity.Recent studies have demonstrated that, RIG-I and MDA5, two cytosolic PRRs, specifically detect viral RNAs that are produced during viral replication. Binding of RIG-I/MDA5 to viral RNA leads to recruitment of a downstream adaptor protein VISA. The mitochondrial outer membrane protein VISA acts as a critical adapter for assembling a virus-induced complex that signals NF-κB and IRF3 activation. However, the components of the VISA-associated complex and their roles in antiviral response are not fully understood yet.Using a biochemical purification approach, we identified the WD repeat protein WDR5 as a VISA-associated protein. WDR5 was recruited to VISA in a viral infection dependent manner. Viral infection also caused translocation of WDR5 from the nucleus to mitochondria. Knockdown of WDR5 impaired the formation of virus-induced VISA-associated complex. Consistently, knockdown of WDR5 inhibited virus-triggered activation of IRF3 and NF-κB as well as transcription of the IFNB1 gene. These findings suggest that WDR5 is essential in assembling a virus-induced VISA-associated complex and plays an important role in virus-triggered induction of typeⅠIFNs.