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A negative feedback modulator of antigen processing evolved from a frameshift in the cowpox virus genome

Lin, J, Eggensperger, S, Hank, S, Wycisk, AI, Wieneke, R, Mayerhofer, PU and Tampé, R (2014) A negative feedback modulator of antigen processing evolved from a frameshift in the cowpox virus genome PLoS Pathog, 10.

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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.

Item Type: Article
Divisions : Surrey research (other units)
Authors :
Lin, J
Eggensperger, S
Hank, S
Wycisk, AI
Wieneke, R
Tampé, R
Date : 2014
DOI : 10.1371/journal.ppat.1004554
Uncontrolled Keywords : ATP-Binding Cassette Transporters/*genetics/immunology/physiology Amino Acid Sequence Animals Antigens, Viral/*genetics/immunology/physiology Cowpox virus/*genetics Endoplasmic Reticulum Feedback, Physiological/physiology Frameshift Mutation/*genetics Genome, Viral/*genetics HeLa Cells Histocompatibility Antigens Class I/immunology Humans Molecular Sequence Data Sf9 Cells
Related URLs :
Depositing User : Symplectic Elements
Date Deposited : 17 May 2017 10:42
Last Modified : 24 Jan 2020 19:52

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