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Molecular Biology Graduate Program and Departments of
Microbiology and
Internal Medicine, University of Iowa, Iowa City, IA 52242; and
Veterans Affairs Medical Center, Iowa City, IA 52242
Latent membrane protein 1 (LMP1) is an EBV-encoded transforming
protein that strongly mimics the B cell-activating properties of a
normal cellular membrane protein, CD40. LMP1 and CD40 both associate
with the cytoplasmic adapter proteins called TNFR-associated factors
(TRAFs). TRAFs 1, 2, and 3 bind to a region of LMP1 that is essential
for EBV to transform B lymphocytes, carboxyl-terminal activating region
(CTAR) 1. However, studies of transiently overexpressed LMP1 molecules,
primarily in epithelial cells, indicated that a second region, CTAR2,
is largely responsible for LMP1-mediated activation of NF-
B and
c-Jun N-terminal kinase. To better understand LMP1 signaling in
B lymphocytes, we performed a structure-function analysis of the LMP1
C-terminal cytoplasmic domain stably expressed in B cell lines. Our
results demonstrate that LMP1-stimulated Ig production, surface
molecule up-regulation, and NF-
B and c-Jun N-terminal kinase
activation require both CTAR1 and CTAR2, and that these two regions may
interact to mediate LMP1 signaling. Furthermore, we find that the
function of CTAR1, but not CTAR2, correlates with TRAF binding and
present evidence that as yet unidentified cytoplasmic proteins may
associate with LMP1 to mediate some of its signaling
activities.
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