Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 193, Issue 8, Pages 943-954Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.193.8.943
Keywords
HHV4; CD40; signal transduction; B lymphocyte; lymphoma
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Funding
- NCI NIH HHS [CA66570] Funding Source: Medline
- NIAID NIH HHS [AI28847] Funding Source: Medline
- NIDDK NIH HHS [DK25295] Funding Source: Medline
- NIGMS NIH HHS [T32 GM007337] Funding Source: Medline
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Latent membrane protein 1 (LMP1) plays a critical role in B cell transformation by Epstein-Barr virus (EBV) and appears to mimic a constitutively active CD40 receptor. Intracellular tumor necrosis factor (TNF) receptor-associated factor (TRAF) adapter proteins, shown to contribute to signaling by both CD40 and LMP1, were recruited by both molecules to lipid-enriched membrane rafts. However. me found that TRAFs 2 and 3 were subsequently degraded after CD40- but not LMP1-induced signaling. This degradation was proteasome-dependent and required direct TRAF binding by CD40. Using a model system designed to directly compare the signaling potency of the cytoplasmic domains of LMP1 and CD40 in B lymphocytes, we found that LMP1 more potently activates c-Jun kinase and nuclear factor kappaB and induces higher levels of several B cell effector functions than does CD40. This suggests that LMP1 utilizes a modified CD40 signaling pathway. Failure to regulate TRAFs may contribute to the enhanced capacity of LMP1 to activate B cells as well as promote B cell transformation.
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