Porcine circovirus type 2 infection attenuates the K63-linked ubiquitination of STING to inhibit IFN-β induction via p38-MAPK pathway

Porcine circovirus 2 (PCV2) has been proved to increase the risk of other pathogens infection via immunosuppression. Although the co-infection of PCV2 and porcine parvovirus (PPV) is commonly observed in worldwide, the relative immune mechanisms promoting PPV infection in PCV2-infected piglets are currently unknown. Herein, we found that PCV2 infection suppressed IFN-beta expression and promoted PPV infection in the piglets. Consistent with this finding, we confirmed that PCV2 infection significantly inhibited the induction of IFN-beta to promote PPV replication in cell level. Furthermore, PCV2 infection attenuated the K63-linked ubiquitination of STING induced by PPV, blocked the formation of complex of STING, TBK1 and IRF3, and further prevented the phosphorylation of TBK1 and IRF3, resulting in a decreased IFN-beta transcription response to PPV infection. Consistently, using cGAMP to direct stimulate STING also appeared a reduced STING-K63 ubiquitination and IFN-beta induction in PCV2-infected cells. However, we noted that knockdown of p38-MAPK signaling could markedly attenuate the inhibitory effect of PCV2 on STING-K63 ubiquitination, and improve the induction of IFN-beta in PCV2-infected whenever theses cells were challenged with PPV infection or cGAMP stimulation. Meanwhile, we found that PCV2 infection promoted the phosphorylation of USP21 to inhibit the K63 ubiquitination of STING and the transcription of IFN-beta via activation of p38-MAPK signaling. Taken together, our results demonstrate that PCV2 infection activates the p38-MAPK signaling pathway-mediated USP21 phosphorylation to inhibit the K63 ubiquitination of STING, which prevents the phosphorylation and transportation to the nucleus of IRF3, leading to an increase risk for PPV infection.

Automated summary

PCV2 infection suppresses IFN-beta expression to promote PPV infection in piglets. Additionally, PCV2 activation of p38-MAPK signaling pathway-mediated USP21 phosphorylation inhibits K63 ubiquitination of STING, leading to an increased risk of PPV infection.