A negative feedback modulator of antigen processing evolved from a frameshift in the cowpox virus genome
- 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.
Author: | Jiacheng LinGND, Sabine Eggensperger, Susanne Hank, Agnes Isabella WyciskGND, Ralph WienekeORCiDGND, Peter Uli MayerhoferORCiDGND, Robert TampéORCiDGND |
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URN: | urn:nbn:de:hebis:30:3-363830 |
DOI: | https://doi.org/10.1371/journal.ppat.1004554 |
ISSN: | 1553-7374 |
ISSN: | 1553-7366 |
Pubmed Id: | https://pubmed.ncbi.nlm.nih.gov/25503639 |
Parent Title (English): | PLoS pathogens |
Publisher: | PLoS |
Place of publication: | Lawrence, Kan. |
Document Type: | Article |
Language: | English |
Date of Publication (online): | 2014/12/11 |
Date of first Publication: | 2014/12/11 |
Publishing Institution: | Universitätsbibliothek Johann Christian Senckenberg |
Release Date: | 2015/01/16 |
Volume: | 10 |
Issue: | (12):e1004554 |
Page Number: | 14 |
Note: | Copyright: © 2014 Lin et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/ , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
HeBIS-PPN: | 367458829 |
Institutes: | Biochemie, Chemie und Pharmazie / Biochemie und Chemie |
Exzellenzcluster / Exzellenzcluster Makromolekulare Komplexe | |
Dewey Decimal Classification: | 5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie |
Sammlungen: | Universitätspublikationen |
Sammlung Biologie / Sondersammelgebiets-Volltexte | |
Licence (German): | Creative Commons - Namensnennung 4.0 |