Abstract：
The Orthopoxvirus (OPXV) genus of the Poxviridae includes human pathogens variola virus (VARV), monkeypox virus (MPXV), vaccinia virus (VACV), and a number of zoonotic viruses. A number of Bcl-2-like proteins of VACV are involved in escaping the host innate immunity. However, little work has been devoted to the evolution and function of their orthologues in other OPXVs. Here, we found that MPXV protein P2, encoded by the P2L gene, and P2 orthologues from other OPXVs, such as VACV protein N2, localize to the nucleus and antagonize interferon (IFN) production. Exceptions to this were the truncated P2 orthologues in camelpox virus (CMLV) and taterapox virus (TATV) that lacked the nuclear localization signal (NLS). Mechanistically, the NLS of MPXV P2 interacted with karyopherin α-2 (KPNA2) to facilitate P2 nuclear translocation, and competitively inhibited KPNA2-mediated IRF3 nuclear translocation and downstream IFN production. Deletion of the NLS in P2 or orthologues significantly enhanced IRF3 nuclear translocation and innate immune responses, thereby reducing viral replication. Moreover, deletion of NLS from N2 in VACV attenuated viral replication and virulence in mice. These data demonstrate that the NLS-mediated translocation of P2 is critical for P2-induced inhibition of innate immunity. Our findings contribute to an in-depth understanding of the mechanisms of OPXV P2 orthologue in innate immune evasion.
摘要：
Poxviridae的正痘病毒（OPXV）属包括人类病原体天花病毒（VARV），猴痘病毒(MPXV),痘苗病毒（VACV），和一些人畜共患病毒。VACV的许多Bcl-2样蛋白参与逃避宿主先天免疫。然而,在其他OPXVs中，很少有工作致力于其直系同源物的进化和功能。这里,我们发现由P2L基因编码的MPXV蛋白P2,和来自其他OPXV的P2直系同源物，例如VACV蛋白N2,定位于细胞核并拮抗干扰素(IFN)的产生。例外的是缺少核定位信号（NLS）的骆驼痘病毒（CMLV）和taterapox病毒（TATV）中的截短的P2直向同源物。机械上,MPXVP2的NLS与核蛋白α-2（KPNA2）相互作用以促进P2核易位，并竞争性抑制KPNA2介导的IRF3核易位和下游IFN的产生。在P2或直系同源物中NLS的缺失显着增强IRF3核易位和先天免疫反应，从而减少病毒复制。此外，在VACV中从N2中缺失NLS减弱了小鼠中的病毒复制和毒力。这些数据表明，NLS介导的P2易位对于P2诱导的先天免疫抑制至关重要。我们的发现有助于深入了解OPXVP2直向同源物在先天免疫逃避中的机制。
