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Blood, 15 February 2008, Vol. 111, No. 4, pp. 2280-2289.
Prepublished online as a Blood First Edition Paper on November 27, 2007; DOI 10.1182/blood-2007-07-100032.
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Submitted July 9, 2007
Accepted November 20, 2007
The LMP1 oncogene of EBV activates PERK and the
unfolded protein response to drive its own synthesis
Dong Yun Lee and Bill Sugden*
McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI, United States
* Corresponding author; email: sugden{at}oncology.wisc.edu.
The oncogene, Latent Membrane Protein 1 (LMP1), of Epstein Barr virus, without a ligand drives proliferation of EBV-infected B-cells. Its levels vary in cells of clonal populations by more than 100-fold, which leads to multiple distinct activities of the oncogene. At intermediate levels it drives proliferation and at high levels it inhibits general protein synthesis by inducing phosphorylation of eukaryotic initiation factor 2 (eIF2). We have found that LMP1 activates PERK to induce phosphorylation of eIF2, which up-regulates ATF4 expression. ATF4, in turn, transactivates LMP1's own promoter. LMP1 activates not only PERK but also IRE1 and ATF6, three pathways of the unfolded protein response, UPR. Increasing levels of expression of LMP1 induced a dose-dependent increase in IRE1 activity as measured by its "splicing" of XBP-1. These infected B-cells secrete immunoglobins independent of the levels of LMP1 indicating only a threshold level of XBP-1 is required for the secretion. These findings indicate that LMP1's activation of the UPR is a normal event in a continuum of LMP1’s expression that leads both to stimulatory and inhibitory functions and regulates the physiology of EBV-infected B-cells in multiple, unexpected modes.
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