CCCH-zinc finger antiviral protein (ZAP) can recognize and induce the degradation of mRNAs and proteins of certain viruses, as well as exert its antiviral activity by activating T cell. However, the mechanism of ZAP mediating T cell activation during virus infection remains unclear. Here, we found a potential function of ZAP that relieves immunosuppression of T cell induced by avian leukosis virus subgroup J (ALV-J) via a novel signaling pathway that involves norbin like protein (NLP), protein kinase C delta (PKC-δ) and nuclear factor of activated T cell (NFAT). Specifically, ZAP expression activated T cells by promoting the dephosphorylation and nuclear translocation of NFAT. Furthermore, knockdown of ZAP weakened the reactivity and antiviral response of T cells. Mechanistically, ZAP reduced PKC-δ activity by up-regulating and reactivating NLP through competitively binding with viral protein. Knockdown of NLP decreased the dephosphorylation of PKC-δ by ZAP expression. Moreover, we showed that knockdown of PKC-δ reduced the phosphorylation levels of NFAT and enhanced its nuclear translocation. Taken together, these data revealed that ZAP relieves immunosuppression caused by ALV-J and mediates T cell activation through NLP–PKC-δ–NFAT pathway.
Importance
The evolution of host defense system is driven synchronously in the process of resisting virus invasion. Accordingly, host innate defense factors exert effectively work in suppressing virus replication. However, it remains unclear that whether the host innate defense factors are involved in antiviral immune response against the invasion of immunosuppressive viruses. Here, we found that CCCH-type zinc finger antiviral protein (ZAP) effectively worked in resistance on immunosuppression caused by avian leukosis virus subgroup J (ALV-J), a classic immunosuppressive virus. Evidence showed that ZAP released the phosphatase activity of NLP inhibited by ALV-J and further activated NFAT by inactivating PKC-δ. This novel molecular mechanism that ZAP regulates antiviral immune response by mediating NLP–PKC-δ–NFAT pathway has greatly enriched the understanding of the functions of host innate defense factors and provided important scientific ideas and theoretical basis for the research of immunosuppressive virus and antiviral immunity.
Inhibition of Japanese encephalitis virus infection by the host zinc-finger antiviral protein
