Diverse cytomegalovirus US11 antagonism and MHC- A evasion strategies reveal a tit- for- tat coevolutionary arms race in hominids

• 成果类型: Article
• 署名作者: Zimmermann, Cosima; Watson, Gabrielle M.; Bauersfeld, Liane; Berry, Richard; Ciblis, Barbara; Lan, Huan; Gerke, Carolin; Oberhardt, Valerie; Fuchs, Jonas; Hofmann, Maike; Freund, Christian; Rossjohn, Jamie; Momburg, Frank; Hengel, Hartmut; Halenius, Anne
• 署名单位: University of Freiburg; Monash University; Monash University; Free University of Berlin; University of Freiburg; University of Freiburg; Cardiff University; Helmholtz Association; German Cancer Research Center (DKFZ)
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14946
• DOI: 10.1073/pnas.2315985121
• 发表日期: 2024-02-27
• 关键词: class-i molecules; endoplasmic-reticulum; hla-a; EVOLUTION; protein; alleles; us6; identification; specificity; RECOGNITION

摘要

Recurrent, ancient arms races between viruses and hosts have shaped both host immu-nological defense strategies as well as viral countermeasures. One such battle is waged by the glycoprotein US11 encoded by the persisting human cytomegalovirus. US11 mediates degradation of major histocompatibility class I (MHC- I) molecules to prevent CD8+ T- cell activation. Here, we studied the consequences of the arms race between US11 and primate MHC- A proteins, leading us to uncover a tit-for-tat coevolution and its impact on MHC- A diversification. We found that US11 spurred MHC- A adaptation to evade viral antagonism: In an ancestor of great apes, the MHC- A A2 lineage acquired a Pro184Ala mutation, which confers resistance against the ancestral US11 targeting strategy. In response, US11 deployed a unique low- complexity region (LCR), which exploits the MHC- I peptide loading complex to target the MHC- A2 peptide- binding groove. In addition, the global spread of the human HLA- A*02 allelic family prompted US11 to employ a superior LCR strategy with an optimally fitting peptide mimetic that specifically antagonizes HLA- A*02. Thus, despite cytomegaloviruses low pathogenic potential, the increasing commitment of US11 to MHC- A has significantly promoted diversification of MHC- A in hominids.