Lee James, Manon Victor, Chen Jue
Laboratory of Membrane Biophysics and Biology, The Rockefeller University, New York, NY 10065.
HHMI, Chevy Chase, MD 20815.
Proc Natl Acad Sci U S A. 2025 Sep 23;122(38):e2516676122. doi: 10.1073/pnas.2516676122. Epub 2025 Sep 16.
In the host-pathogen arms race, herpesviruses and poxviruses encode proteins that sabotage the transporter associated with antigen processing (TAP), thereby suppressing MHC-I antigen presentation and enabling lifelong infection. Of the five known viral TAP inhibitors, only the herpes simplex virus (HSV) protein ICP47 has been structurally resolved. We now report cryoelectron microscopy structures of TAP in complex with the remaining four: BNLF2a (Epstein-Barr virus), hUS6 (human cytomegalovirus), bUL49.5 (bovine herpesvirus 1), and CPXV012 (cowpox virus), assembling a structural atlas of viral TAP evasion. Despite employing divergent sequences, folds, and conformational targets, these viral inhibitors converge on a common strategy: they stall TAP from the alternating access cycle, precluding peptide entry into the ER and shielding infected cells from cytotoxic T cell surveillance. These findings reveal striking functional convergence and provide a structural framework for rational antiviral design.
在宿主与病原体的军备竞赛中，疱疹病毒和痘病毒编码破坏与抗原加工相关转运体（TAP）的蛋白质，从而抑制MHC-I抗原呈递并实现终身感染。在已知的五种病毒TAP抑制剂中，只有单纯疱疹病毒（HSV）蛋白ICP47的结构得到了解析。我们现在报告了TAP与其余四种蛋白形成复合物的冷冻电镜结构：BNLF2a（爱泼斯坦-巴尔病毒）、hUS6（人巨细胞病毒）、bUL49.5（牛疱疹病毒1型）和CPXV012（牛痘病毒），构建了病毒TAP逃避的结构图谱。尽管这些病毒抑制剂采用了不同的序列、折叠方式和构象靶点，但它们都采用了一种共同策略：使TAP停止交替转运循环，阻止肽进入内质网，并保护受感染细胞免受细胞毒性T细胞监测。这些发现揭示了显著的功能趋同，并为合理的抗病毒设计提供了结构框架。
