Lin Jiacheng, Eggensperger Sabine, Hank Susanne, Wycisk Agnes I, Wieneke Ralph, Mayerhofer Peter U, Tampé Robert
Institute of Biochemistry, Biocenter, Goethe-University Frankfurt, Frankfurt, Germany.
Institute of Biochemistry, Biocenter, Goethe-University Frankfurt, Frankfurt, Germany; Cluster of Excellence - Macromolecular Complexes, Goethe-University Frankfurt, Frankfurt, Germany.
PLoS Pathog. 2014 Dec 11;10(12):e1004554. doi: 10.1371/journal.ppat.1004554. eCollection 2014 Dec.
Coevolution of viruses and their hosts represents a dynamic molecular battle between the immune system and viral factors that mediate immune evasion. After the abandonment of smallpox vaccination, cowpox virus infections are an emerging zoonotic health threat, especially for immunocompromised patients. Here we delineate the mechanistic basis of how cowpox viral CPXV012 interferes with MHC class I antigen processing. This type II membrane protein inhibits the coreTAP complex at the step after peptide binding and peptide-induced conformational change, in blocking ATP binding and hydrolysis. Distinct from other immune evasion mechanisms, TAP inhibition is mediated by a short ER-lumenal fragment of CPXV012, which results from a frameshift in the cowpox virus genome. Tethered to the ER membrane, this fragment mimics a high ER-lumenal peptide concentration, thus provoking a trans-inhibition of antigen translocation as supply for MHC I loading. These findings illuminate the evolution of viral immune modulators and the basis of a fine-balanced regulation of antigen processing.
病毒与其宿主的共同进化代表了免疫系统与介导免疫逃逸的病毒因子之间动态的分子较量。在停止天花疫苗接种后，牛痘病毒感染成为一种新出现的人畜共患病健康威胁，尤其对于免疫功能低下的患者。在此，我们阐述了牛痘病毒CPXV012干扰MHC I类抗原加工的机制基础。这种II型膜蛋白在肽结合和肽诱导的构象变化之后的步骤抑制核心TAP复合体，从而阻断ATP结合和水解。与其他免疫逃逸机制不同，TAP抑制由CPXV012的一个短内质网腔片段介导，这是牛痘病毒基因组中移码的结果。该片段锚定在内质网膜上，模拟内质网腔中高浓度的肽，从而引发对抗原转运的反式抑制，作为MHC I装载的供应。这些发现阐明了病毒免疫调节剂的进化以及抗原加工精细平衡调节的基础。
Zotero 插件
