SPI-2/CrmA inhibits IFN-β induction by targeting TBK1/IKKε

Viruses modulate the host immune system to evade host antiviral responses. The poxvirus proteins serine proteinase inhibitor 2 (SPI-2) and cytokine response modifier A (CrmA) are involved in multiple poxvirus evasion strategies. SPI-2 and CrmA target caspase-1 to prevent apoptosis and cytokine activation. Here, we identified SPI-2 and CrmA as negative regulators of virus-triggered induction of IFN-β. Ectopic expression of SPI-2 or CrmA inhibited virus-triggered induction of IFN-β and its downstream genes. Consistently, knockdown of SPI-2 by RNAi potentiated VACV-induced transcription of antiviral genes. Further studies revealed that SPI-2 and CrmA associated with TBK1 and IKKe to disrupt the MITA-TBK1/IKKe-IRF3 complex. These findings reveal a novel mechanism of SPI-2/CrmA-mediated poxvirus immune evasion.