A Negative Feedback Modulator of Antigen Processing Evolved from a Frameshift in the Cowpox Virus Genome

PLoS Pathogens

Robert Tampé¹  Susanne Hank¹  Jiacheng Lin¹  Sabine Eggensperger¹  Ralph Wieneke¹  Agnes I. Wycisk¹  Peter U. Mayerhofer¹ 

[1] Institute of Biochemistry, Biocenter, Goethe-University Frankfurt, Frankfurt, Germany

关键词: Antigen presentation;    Major histocompatibility complex;    Immunoprecipitation;    Immunoblotting;    Antigen processing;    recognition;    Cross-linking;    Cowpox virus;    Immune system proteins;   

DOI  :  10.1371/journal.ppat.1004554

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY