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LMP1 TRAFficking Activates Growth and Survival pathways

  • Chapter
TNF Receptor Associated Factors (TRAFs)

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 597))

Abstract

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 clumping, which are characteristic of CD40 activated B lymphocytes. In immortalized fibroblasts, LMP1 mimics aspects of activated ras in enbling 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-κB, 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, IKKα and p52 mediated noncanonical NF-κB pathway and LMP1 TES2/CTAR2 activates TRAF6, TAB1, TAK1, IKKα/IKKβ/IKKγ mediated canonical NF-κB pathway. Interestingly, TRAF3 is a negative regulator of noncanonical NF-κB 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-κB 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.

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Authors and Affiliations

  1. Channing Laboratory and Infectious Disease Division, Department of Medicine, Brigham and Women’s Hospital, 181 Longwood Avenue, Boston, Massachusetts, 02115, USA

    Elliott Kieff

  2. Department of Microbiology and Molecular Genetics, Harvard Medical School and University, 181 Longwood Avenue, Boston, Massachusetts, 02115, USA

    Elliott Kieff

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  1. Vishal Soni
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  2. Ellen Cahir-McFarland
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  3. Elliott Kieff
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  1. Department of Biochemistry, Weill Medical College of Cornell University, New York, New York, USA

    Hao Wu Ph.D.

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Soni, V., Cahir-McFarland, E., Kieff, E. (2007). LMP1 TRAFficking Activates Growth and Survival pathways. In: Wu, H. (eds) TNF Receptor Associated Factors (TRAFs). Advances in Experimental Medicine and Biology, vol 597. Springer, New York, NY. https://doi.org/10.1007/978-0-387-70630-6_14

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