title: A negative feedback modulator of antigen processing evolved from a frameshift in the cowpox virus genome.
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.
authors.affiliation: Institute of Biochemistry, Biocenter, Goethe-University Frankfurt, Frankfurt, Germany.
authors.forename: Jiacheng
authors.initials: J
authors.lastname: Lin
authors.affiliation: Institute of Biochemistry, Biocenter, Goethe-University Frankfurt, Frankfurt, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Eggensperger
authors.affiliation: Institute of Biochemistry, Biocenter, Goethe-University Frankfurt, Frankfurt, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Hank
authors.affiliation: Institute of Biochemistry, Biocenter, Goethe-University Frankfurt, Frankfurt, Germany.
authors.forename: Agnes I
authors.initials: AI
authors.lastname: Wycisk
authors.affiliation: Institute of Biochemistry, Biocenter, Goethe-University Frankfurt, Frankfurt, Germany.
authors.forename: Ralph
authors.initials: R
authors.lastname: Wieneke
authors.affiliation: Institute of Biochemistry, Biocenter, Goethe-University Frankfurt, Frankfurt, Germany.
authors.forename: Peter U
authors.initials: PU
authors.lastname: Mayerhofer
authors.affiliation: Institute of Biochemistry, Biocenter, Goethe-University Frankfurt, Frankfurt, Germany; Cluster of Excellence - Macromolecular Complexes, Goethe-University Frankfurt, Frankfurt, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Tampé
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000276:immunology / Q000502:physiology; D000595:Amino Acid Sequence; D000818:Animals; D000956:Antigens, Viral / Q000235:genetics* / Q000276:immunology / Q000502:physiology; D015608:Cowpox virus / Q000235:genetics*; D004721:Endoplasmic Reticulum; D025461:Feedback, Physiological / Q000502:physiology; D016368:Frameshift Mutation / Q000235:genetics*; D016679:Genome, Viral / Q000235:genetics*; D006367:HeLa Cells; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D008969:Molecular Sequence Data; D061987:Sf9 Cells
chemical_list: D018528:ATP-Binding Cassette Transporters; D000956:Antigens, Viral; D015395:Histocompatibility Antigens Class I; C477327:transporter associated with antigen processing (TAP)