The nested open reading frame in the Epstein-Barr virus nuclear antigen-1 mRNA encodes a protein capable of inhibiting antigen presentation in cis

Martine Ossevoort, Arnaud Zaldumbide, Aartjan J.W. te Velthuis, Mark Melchers, Maaike E. Ressing, Emmanuel J.H.J. Wiertz, Rob C. Hoeben

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Herpesviruses employ many mechanisms to evade the immune response, allowing them to persist life-long in their hosts. The Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA-1) and, more recently, the latency-associated nuclear antigen 1 (LANA-1) of the Kaposi Sarcoma Herpesvirus have been shown to function as in cis-acting inhibitors of antigen presentation. In both proteins, long simple repeat elements are responsible for the inhibition, but the sequences of these repeats are strongly dissimilar. Intriguingly, EBNA-1 mRNA contains a large nested open reading frame that codes for a 40.7 kDa strongly acidic protein, in addition to the full-length EBNA-1. This protein, here called pGZr, has a 230 amino-acids long glycine, glutamine, and glutamic acid-rich repeat ('GZ' repeat), highly similar (65% amino-acid identity) to the acidic repeat of LANA-1. To evaluate if pGZr, like EBNA-1 and LANA-1, can inhibit antigen presentation in cis, we fused the nested ORF with the E. coli-derived LacZ gene encoding β-galactosidase. Whereas cells producing the unmodified β-galactosidase readily present the H-2Ld-restricted CTL epitope TPHPARIGL, which resides in the C-terminal region of β-galactosidase, cells producing the pGZr-β-galactosidase fusion protein do not. Also shorter fragments of the repeat can inhibit peptide presentation. Even though the physiological function of pGZr remains to be elucidated, the GZ-repeat protein may be valuable as inhibitor of presentation of antigenic peptides derived from transgenes in gene therapy.

Original languageEnglish (US)
Pages (from-to)3588-3596
Number of pages9
JournalMolecular Immunology
Volume44
Issue number14
DOIs
StatePublished - Jul 2007
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Immunology
  • Molecular Biology

Keywords

  • Antigen
  • Epstein-Barr virus
  • Fusion protein
  • Immune evasion
  • Proteasome

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