Autoactivation of the Epstein-Barr virus oncogenic protein LMP1 during type II latency through opposite roles of the NF-kappaB and JNK signaling pathways.
Epstein-Barr virus (EBV) is associated with several human malignancies where it expresses limited subsets of latent proteins. Of the latent proteins, latent membrane protein 1 (LMP1) is a potent transforming protein that constitutively induces multiple cell signaling pathways and contributes to EBV-associated oncogenesis. Regulation of LMP1 expression has been extensively described during the type III latency of EBV. Nevertheless, in the majority of EBV-associated tumors, the virus is commonly found to display a type II latency program in which it is still unknown which viral or cellular protein is really involved in maintaining LMP1 expression. Here, we demonstrate that LMP1 activates its own promoter pLMP1 through the JNK signaling pathway emerging from the TES2 domain. Our results also reveal that this activation is tightly controlled by LMP1, since pLMP1 is inhibited by LMP1-activated NF-kappaB signaling pathway. By using our physiological models of EBV-infected cells displaying type II latency as well as lymphoblastoid cell lines expressing a type III latency, we also demonstrate that this balanced autoregulation of LMP1 is shared by both latency programs. Finally, we show that this autoactivation is the most important mechanism to maintain LMP1 expression during the type II latency program of EBV.
Goormachtigh
Gautier
G
CNRS UMR 8527, Institut de Biologie de Lille (IBL), 1 rue du Pr. Calmette, 59021 Lille Cedex, France.
Ouk
Tan-Sothéa
TS
Mougel
Alexandra
A
Tranchand-Bunel
Denis
D
Masy
Eric
E
Le Clorennec
Christophe
C
Feuillard
Jean
J
Bornkamm
Georg W
GW
Auriault
Claude
C
Manet
Evelyne
E
Fafeur
Véronique
V
Adriaenssens
Eric
E
Coll
Jean
J
D004789:Enzyme Activation; D004854:Herpesvirus 4, Human / Q000502:physiology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism / Q000821:virology; D008156:Luciferases / Q000378:metabolism; D008214:Lymphocytes / Q000378:metabolism / Q000821:virology; D016328:NF-kappa B / Q000502:physiology*; D015398:Signal Transduction; D014763:Viral Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D017735:Virus Latency
C037662:EBV-associated membrane antigen, Epstein-Barr virus; D016328:NF-kappa B; D014763:Viral Matrix Proteins; D008156:Luciferases; D048031:JNK Mitogen-Activated Protein Kinases