Submitted March 21, 2003
Accepted August 8, 2003
Proteasomal targeting of a viral oncogene abrogates oncogenic phenotype and enhances immunogenicity
Judy Tellam, Geoff Connolly, Natasha Webb, Jaikumar Duraiswamy, and Rajiv Khanna*
Division of Infectious Diseases and Immunology, Queensland Institute of Medical Research, Herston, QLD, Australia
* Corresponding author; email: rajivK{at}qimr.edu.au.
The ability of viral or mutated cellular oncogenes to initiate neoplastic events and their poor immunogenicity has considerably undermined their potential use as immunotherapeutic tools for the treatment of human cancers. Using a Epstein-Barr virus encoded oncogene, latent membrane protein 1 (LMP1) as a model, we report a novel strategy, which both deactivates cellular signaling pathways associated with the oncogenic phenotype and reverses poor immunogenicity. We show that co-translational ubiquitination combined with N-end rule targeting of LMP1 enhanced the intracellular degradation of LMP1 and total blockade of LMP1-mediated NF-
B and STAT activation in human cells. In addition, although murine cells expressing LMP1 were uniformly tumorigenic, this oncogenicity was completely abrogated by covalent linkage of LMP1 with ubiquitin, while an enhanced CD8+ T cell response to a model epitope fused to the C-terminus of LMP1 was observed following immunization with ubiquitinated LMP1. These observations suggest that proteasomal targeting of tumor-associated oncogenes could be exploited therapeutically by either gene therapy or vaccination.
