Avoiding Proteasomal Processing: The Case of EBNA1

Ubiquitin/proteasome-dependent proteolysis is involved in the regulation of a large variety of cellular processes including cell cycle progression, tissue development and atrophy, flux of substrates through metabolic pathways, selective elimination of abnormal proteins and processing of intracellular antigens for major histocompatibility complex (MHC) class I-restricted T-cell responses. Many viruses tamper with this proteolytic machinery by encoding proteins that interact with various components of the pathway. A particularly interesting example of a viral protein that interferes with proteasomal processing is the Epstein-Barr virus (EBV) nuclear antigen-1 (EBNA1). EBNA1 contains an internal repeat exclusively composed of glycines and alanines that inhibits in cis the presentation of MHC class I-restricted T-cell epitopes and prevents ubiquitin/proteasome-dependent proteolysis in vitro and in vivo. The glycine-alanine repeat acts as a transferable element on a variety of proteasomal substrates and may therefore provide a new approach to the modification of cellular proteins for therapeutic purposes.