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

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Virus-infected or malignant transformed cells are eliminated by cytotoxic T lymphocytes, which recognize antigenic peptide epitopes in complex with major histocompatibility complex class I (MHC I) molecules at the cell surface. The majority of such peptides are derived from proteasomal degradation in the cytosol and are then translocated into the ER lumen in an energy-consuming reaction via the transporter associated with antigen processing (TAP), which delivers the peptides onto MHC I molecules as final acceptors. Viruses have evolved sophisticated strategies to escape this immune surveillance. Here we show that the cowpox viral protein CPXV012 inhibits the ER peptide translocation machinery by allosterically blocking ATP binding and hydrolysis by TAP. The short ER resident active domain of the viral protein evolved from a reading frame shift in the cowpox virus genome and exploits the ER-lumenal negative feedback peptide sensor of TAP. This CPXV012-induced conformational arrest of TAP is signaled by a unique communication across the ER membrane to the cytosolic motor domains of the peptide pump. Furthermore, this study provides the rare opportunity to decipher on a molecular level how nature plays hide and seek with a pathogen and its host.

Vyšlo v časopise: A Negative Feedback Modulator of Antigen Processing Evolved from a Frameshift in the Cowpox Virus Genome. PLoS Pathog 10(12): e32767. doi:10.1371/journal.ppat.1004554
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004554

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