The Epstein-Barr virus oncoprotein latent membrane protein 1 induces expression of the chemokine IP-10: Importance of mRNA half-life regulation

The latent membrane protein 1 (LMP1) of Epstein-Barr Virus (EBV) is the main inducer of immuno-modulatory molecules affecting growth and survival of EBV-infected cells. However, the network of signalling pathways involved remains to be elucidated. Here we show that LMP1 may regulate cellular genes like IFN-gamma-inducible protein-10 kDa (IP-10) not only through transcriptional but also post-transcriptional mechanisms. LMP1-mediated IP-10 expression is independent from IFN-gamma, TNF-alpha or IL-18. Transcriptional activation of IP-10 by LMP1 or CD40 stimulation depends on an NF-KB motif within the proximal 435 bp fragment. Carboxy-terminal activating regions 1 or 2 of LMP1 are sufficient to direct IP-10 promoter activation. IP-10 induction is inhibited by blockade of p38/SAPK2 with SB 202190, which results in decreased IP-10 mRNA half-life without affecting IP-10 promoter activity. Thus, LMP1-mediated p38/SAPK2 activation regulates transcript stability. This new mechanism of gene regulation demonstrates the potential of the oncoprotein LMP1 to orchestrate a network of signalling pathways at different regulatory levels including mRNA stability. (C) 2004 Wiley-Liss, Inc.