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 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.
Highlights
Coexistence of pathogens and their hosts represents a masterpiece of evolution, which relies on a fine-tuned balance between pathogen replication and clearance of pathogens by the host immune system [1]
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 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
Summary
Coexistence of pathogens and their hosts represents a masterpiece of evolution, which relies on a fine-tuned balance between pathogen replication and clearance of pathogens by the host immune system [1]. Recognizing virus-specific epitopes displayed on MHC I at the cell surface is the essential step in priming and execution of an adaptive immune response against infection. These antigenic peptide epitopes are derived from degradation of the cellular proteome, including virus or tumor associated gene products, via the ubiquitin-proteasomal pathway. The generated peptides are translocated into the ER lumen by the transporter associated with antigen processing (TAP) and subsequently loaded onto MHC I molecules [5,8] This heterodimeric ATP-binding cassette (ABC) transport complex is composed of two transmembrane domains (TMDs) and two cytosolic nucleotide-binding domains (NBDs), which couple the chemical energy of ATP binding and hydrolysis to the peptide translocation across the ER membrane [9]. TAP can be dissected into the coreTAP complex, which has been shown to be essential and sufficient for peptide translocation, and extra N-terminal transmembrane domains (TMD0), which bind Tsn and are essential for the assembly of the PLC [11,12,13,14]
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