Alpha-herpesvirus UL55 synergizes with ICP27 to suppress type I interferon production through conserved and host-adapted mechanisms
Ying Wu, Mengya Zhang, Anyang Sun, Qiqi Yang, Ruofei An, Mingshu Wang, Shun Chen, Renyong Jia, Mafeng Liu, Qiao Yang, Bin Tian, Xumin Ou, Juan Huang, Di Sun, Dekang Zhu, Xinxin Zhao, Shaqiu Zhang, Yu He, Zhen Wu, Anchun ChengABSTRACT
Herpesviruses employ sophisticated immune evasion strategies to establish lifelong infections, subverting type I interferon (IFN-I) responses critical for antiviral defense. However, their adaptive mechanisms across species remain poorly characterized. Using duck plague virus (DPV)—an avian alphaherpesvirus model—we identify a cooperative immune evasion axis wherein ICP27 orchestrates UL55-mediated immunosuppression through dual regulatory mechanisms: its RNA-binding domain (RGG) facilitates UL55 mRNA nuclear export, while its C-terminal domain (CTD) stabilizes UL55 protein via direct interaction. This partnership enables synergistic suppression of IFN-I signaling—co-expression of ICP27 and UL55 inhibits Poly(I:C)-induced immune genes (IFN-β, Mx, OASL, IL-6) more potently than either protein alone. UL55 functions as a precision-targeted IFN-I antagonist, selectively degrading RIG-I and IRF7 through proteasomal pathways—confirmed by proteasome inhibitor rescue (MG132), structural modeling (AlphaFold), and binding assays (Co-IP). Evolutionarily, UL55 homologs (DPV, Herpes simplex virus type 1 [HSV-1], Varicella zoster virus [VZV]) conserve RIG-I targeting but diverge in IRF3/IRF7 regulation—adaptations shaped by UL55 sequence divergence (38.68% identity) and host biology (e.g., waterfowl IRF3 deficiency). This work establishes ICP27-UL55 as a key regulatory axis in herpesviral immune evasion and redefines UL55 as a conserved yet adaptable immunosuppressor in
IMPORTANCE
This study fundamentally advances herpesvirology by defining a novel immune evasion paradigm in duck plague virus. We reveal ICP27 as a master regulator that coordinates UL55 immunosuppression through a two-tiered mechanism: RGG domain-mediated mRNA nuclear export and CTD-dependent protein stabilization—an unreported strategy in herpesviruses. UL55 selectively degrades RIG-I and IRF7 via proteasomal pathways, enabling precise IFN-I suppression with minimal immune activation. Crucially, ICP27-UL55 synergy inhibits Poly(I:C)-induced immune genes (IFN-β, Mx, OASL, IL-6) more effectively than individual proteins. Evolutionary analyses demonstrate conserved targeting of RIG-I across alphaherpesvirus UL55 homologs (DPV, HSV-1, VZV) but host-adapted divergence in IRF3/IRF7 regulation, shaped by UL55 sequence variation (38.68% identity) and host biology (e.g., avian IRF3 deficiency). These findings provide the first evidence of effector coordination through integrated transcriptional/post-translational regulation in herpesviruses. Disrupting ICP27-UL55 interaction offers new antiviral targets, while UL55-deficient strains serve as vaccine candidates for poultry disease control.