LMP1 TRAFficking activates growth and survival pathways.
Epstein-Barr Virus (EBV) Latent Infection Membrane Protein 1 (LMP1) is expressed in all the EBV related malignancies. LMP1 expression is critical for transformation of human B-cells by EBV. LMP1 expression in human B cells induces activation and adhesion molecule expression and cell dumping, which are characteristic of CD40 activated B lymphocytes. In immortalized fibroblasts, LMP1 mimics aspects of activated ras in enabling serum, contact, and anchorage independent growth. Reverse genetic analyses implicate six transmembrane domains (TM), TM1-6, and two C-terminal cytosolic domains, transformation effector sites 1 and 2 (TES1 and 2) or C-terminal activation regions 1 and 2 (CTAR1 and 2) as the essential domains for LMP1 effects. The 6 transmembrane domains cause intermolecular interaction, whereas the C-terminal domains signal through tumor necrosis factor receptor (TNFR) associated factors (TRAFs) or TNFR associated death domain proteins (TRADD) and activate NF-kappaB, JNK, and p38. LMP1 TES1/CTAR1 directly recruits TRAFs 1, 2, 3 and 5 whereas LMP1 TES2/CTAR2 indirectly recruits TRAF6 via BS69. LMP1 TES1/CTAR1 activates TRAF2, NIK, IKKalpha and p52 mediated noncanonical NF-KB pathway and LMP1 TES2/CTAR2 activates TRAF6, TAB1, TAK1, IKKalpha/ IKKbeta/ IKKgamma mediated canonical NF-KB pathway. Interestingly, TRAF3 is a negative regulator of noncanonical NF-kappaB activation, although a positive role in LMP1 signaling has also been described. LMP1 mediated JNK activation is predominantly TES2/CTAR2 dependent and requires TRAF6. LMP1 specifically increases TRAF3 partitioning into lipid rafts and interestingly does not induce degradation of any of the TRAFs upon NF-kappaB activation. Studies of the chemistry and biology of LMP1-TRAF interaction mediated activation of signaling pathways are important for controlling EBV infected cell survival and growth.
Soni
Vishal
V
Channing Laboratory and Infectious Disease Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School and University, Boston, Massachusetts 02115, USA.
Cahir-McFarland
Ellen
E
Kieff
Elliott
E
D049109:Cell Proliferation; D002470:Cell Survival / Q000502:physiology; D004854:Herpesvirus 4, Human / Q000502:physiology*; D006801:Humans; D015398:Signal Transduction / Q000502:physiology*; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000502:physiology*; D014763:Viral Matrix Proteins / Q000502:physiology*
C037662:EBV-associated membrane antigen, Epstein-Barr virus; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D014763:Viral Matrix Proteins