Epstein-Barr virus latent membrane protein-1 triggers AP-1 activity via the c-Jun N-terminal kinase cascade

The Epstein–Barr virus latent membrane protein‐1 (LMP‐1) is an integral membrane protein which transforms fibroblasts and is essential for EBV‐mediated B‐cell immortalization. LMP‐1 has been shown to trigger cellular NF‐κB activity which, however, cannot fully explain the oncogenic potential of LMP‐1. Here we show that LMP‐1 induces the activity of the AP‐1 transcription factor, a dimer of Jun/Jun or Jun/Fos proteins. LMP‐1 effects on AP‐1 are mediated through activation of the c‐Jun N‐terminal kinase (JNK) cascade, but not the extracellular signal‐regulated kinase (Erk) pathway. Consequently, LMP‐1 triggers the activity of the c‐Jun N‐terminal transactivation domain which is known to be activated upon JNK‐mediated phosphorylation. Deletion analysis indicates that the 55 C‐terminal amino acids of the LMP‐1 molecule, but not its TRAF interaction domain, are essential for AP‐1 activation. JNK‐mediated transcriptional activation of AP‐1 is the direct output of LMP‐1‐triggered signaling, as shown by an inducible LMP‐1 mutant. Using a tetracycline‐regulated LMP‐1 allele, we demonstrate that JNK is also an effector of non‐cytotoxic LMP‐1 signaling in B cells, the physiological target cells of EBV. In summary, our data reveal a novel effector of LMP‐1, the SEK/JNK/c‐Jun/AP‐1 pathway, which contributes to our understanding of the immortalizing and transforming potential of LMP‐1.