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

Journal article

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 40.7kDa 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 beta-galactosidase. Whereas cells producing the unmodified beta-galactosidase readily present the H-2L(d)-restricted CTL epitope TPHPARIGL, which resides in the C-terminal region of beta-galactosidase, cells producing the pGZr-beta-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.

Authors: Ossevoort, M; Zaldumbide, A; te Velthuis, A; Melchers, M; Ressing, M

• Journal: Molecular immunology
• Volume: 44
• Issue: 14
• Pages: 3588-3596
• Publication date: 2007-07-01
• DOI: 10.1016/j.molimm.2007.03.005
• EISSN: 1872-9142
• ISSN: 0161-5890
• Language: English
• Keywords: Amino Acid Sequence; Molecular Sequence Data; Epstein-Barr Virus Nuclear Antigens; Open Reading Frames; Humans; Cell Line; Mice; Recombinant Fusion Proteins; Antigen Presentation; beta-Galactosidase; Base Sequence; RNA, Messenger; Peptides; T-Lymphocytes, Cytotoxic; Animals; Viral Proteins