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LMP1 TRAFficking activates growth and survival pathways
Vishal Soni1, Ellen Cahir-McFarland, Elliott Kieff
1Channing Laboratory and Infectious Disease Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School and University, Boston, Massachusetts 02115, USA.
Advances in Experimental Medicine and Biology
|July 18, 2007
Summary
Epstein-Barr Virus (EBV) Latent Membrane Protein 1 (LMP1) drives EBV-related cancers by activating key cell signaling pathways. Understanding LMP1
Area of Science:
- Virology
- Molecular Biology
- Oncology
Background:
- Epstein-Barr Virus (EBV) is linked to various malignancies.
- Latent Membrane Protein 1 (LMP1) is crucial for EBV-driven cell transformation.
- LMP1 mimics CD40 activation in B cells and Ras activation in fibroblasts.
Purpose of the Study:
- To elucidate the molecular mechanisms of LMP1-mediated cell signaling.
- To identify the essential domains within LMP1 responsible for its biological effects.
- To investigate the role of LMP1 in activating NF-kappaB, JNK, and p38 pathways.
Main Methods:
- Reverse genetic analyses to identify critical LMP1 domains (TM1-6, TES1/CTAR1, TES2/CTAR2).
- Investigation of LMP1 interactions with Tumor Necrosis Factor Receptor (TNFR)-associated factors (TRAFs) and TNFR-associated death domain proteins (TRADD).
- Analysis of LMP1-mediated activation of canonical and noncanonical NF-kappaB pathways, and JNK signaling.
Main Results:
- LMP1's six transmembrane domains mediate intermolecular interactions.
- C-terminal domains (TES1/CTAR1, TES2/CTAR2) signal through TRAFs/TRADD, activating NF-kappaB, JNK, and p38.
- TES1/CTAR1 recruits TRAFs 1, 2, 3, 5 and activates noncanonical NF-kappaB; TES2/CTAR2 recruits TRAF6 and activates canonical NF-kappaB and JNK.
- TRAF3's role in LMP1 signaling is complex, acting as a negative regulator of noncanonical NF-kappaB but also showing a positive role.
Conclusions:
- LMP1 utilizes distinct C-terminal domains to engage specific TRAFs and activate canonical and noncanonical NF-kappaB pathways.
- LMP1-mediated JNK activation is primarily dependent on TES2/CTAR2 and TRAF6.
- Understanding LMP1-TRAF interactions is vital for developing strategies against EBV-infected cell survival and growth.
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