Picornavirus VP2 protein suppresses innate immunity through selective autophagic degradation of IKBKE/IKKε

Senecavirus A (SVA) belongs to the picornaviruses and has emerged as a promising candidate for oncolytic virotherapy in humans. Understanding the immune suppression mechanisms employed by SVA can help optimize its therapeutic efficacy as an oncolytic virus while simultaneously minimizing its immune suppressive effects on normal tissues. In this study, we identified a novel function of the SVA structural protein VP2 as a key viral immune suppressive factor during SVA infection. VP2 targets and degrades IKBKE/IKKε, a key component of the innate immune pathway, thereby suppressing host innate immune responses. It preferentially interacts with the selective autophagic receptor CALCOCO2/NDP52 (calcium binding and coiled-coil domain 2), which then recognizes the K33-linked ubiquitinated IKBKE and delivers it to phagophores for degradation. The E3 ligase RNF114 is responsible for catalyzing the K33-linked ubiquitination of IKBKE at Lys490, and VP2 significantly promoted this modification, which further accelerated IKBKE degradation. Importantly, we found that picornavirus VP2 proteins share this conserved mechanism in degradation of IKBKE and suppression of host innate immunity. These data elucidate the negative regulatory mechanism involving the VP2-RNF114-IKBKE/IKKε-CALCOCO2 axis, and reveal an immune evasion strategy employed by picornaviruses. These findings will provide valuable insights for the development of picornaviral vaccines and antiviral/antitumor therapeutics.