After coexpression of Touch1, TAP2, flagCPXV012, and either US6myc (Fig. underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information files. Abstract 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 computer 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 switch, in blocking ATP binding and hydrolysis. Distinct from other immune evasion mechanisms, TAP inhibition is AZ-33 usually mediated by a short ER-lumenal fragment of CPXV012, which results from a frameshift in the cowpox computer 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 development of viral immune modulators and the basis of a fine-balanced regulation of antigen processing. Author Summary Virus-infected or malignant transformed cells are eliminated by cytotoxic T lymphocytes, which identify 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 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 this 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 developed from a reading frame shift in the cowpox computer virus genome and exploits the ER-lumenal unfavorable opinions peptide sensor of TAP. Rabbit Polyclonal to PE2R4 This CPXV012-induced conformational arrest of TAP is usually 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. Introduction Coexistence of pathogens and their hosts represents a masterpiece of development, which relies on a fine-tuned balance between pathogen replication and clearance of pathogens by the host immune system . To escape immune surveillance, viruses have developed sophisticated strategies , . For example, Herpes simplex viruses and varicella-zoster computer virus establish latency in trigeminal and dorsal root ganglia, which express only low levels of major histocompatibility complex class I (MHC I) molecules , , . Exploitation refers to memory T-cells that circulate through the body and hence provide excellent vehicles for computer virus dissemination during main simian varicella computer virus contamination . Sabotage is usually mediated by a C-type lectin-like gene product of cytomegalovirus that functions as a decoy ligand to subvert missing-self acknowledgement by natural killer cells (NK), thereby circumventing the removal of the computer virus infected cell , . Realizing virus-specific epitopes displayed on MHC I at the cell surface is the essential step in priming AZ-33 and execution of an adaptive immune response against contamination. These antigenic peptide epitopes are derived from degradation AZ-33 of the cellular proteome, including computer virus or tumor associated gene products, the ubiquitin-proteasomal pathway. The generated peptides are translocated into the ER.