EBV Conference 2008 Guangzhou - Baylor College of Medicine

134 (RegID: 1235)
Khilan Shah
Institution: CRUK Institute for Cancer Studies, School of Cancer Sciences, University of Birmingham
e-mail: shahkm@bham.ac.uk
THE EPSTEIN-BARR VIRUS (EBV)-ENCODED LMP2A AND LMP2B PROTEINS MODULATE
INTERFERON SIGNALLING IN HUMAN EPITHELIAL CELLS.
K.M.Shah, S.E.Stewart, S.F.Murphy, W.Wei, C.Woodman, C.W.Dawson and L.S.Young
Cancer Research (UK) Institute for Cancer Studies, University of Birmingham, Birmingham, B15 2TT,
UK
Posterabstract:
Whilst the association of Epstein-Barr virus (EBV) with the development of certain carcinomas is well
documented, the precise role that individual EBV gene products play in the carcinogenic process remains
unknown. The EBV-encoded latent membrane 2A (LMP2A) and LMP2B proteins are frequently
expressed in EBV-positive carcinomas (NPC and gastric adenocarcinoma), suggesting that they play an
essential role in epithelial cell growth transformation or in the maintenance of the virus-transformed state.
Our recent findings have uncovered a novel function for these proteins in epithelial cells, namely, their
ability to modulate signalling from type I and type II interferon receptors. We found that
LMP2A/2B-expressing epithelial cells showed decreased responsiveness to interferon (IFN- � and
IFN- �) as assessed by STAT1 phosphorylation, ISGF3 and GAF-mediated
binding to ISRE and GAS
elements, and ISRE/GAS luciferase reporter activation. Microarray profiling and Q-PCR validation
showed that the effect of LMP2A and LMP2B on interferon-stimulated gene expression was “global”,
with both proteins attenuating the induction of a many IFN-stimulated target genes. Although the levels of
cell surface interferon receptors were similar between control, LMP2A and LMP2B-expressing cells, we
found that the rates of interferon receptor degradation were significantly increased in the presence of
LMP2A and LMP2B. Further analysis revealed that this function was attributed to increased endocytosis
and lysosomal degradation of IFNRs. Preliminary investigations have uncovered a role for endosome
acidification in this process as chloroquine, an endosomal acidification inhibitor, blocked the effects of
LMP2A and LMP2B on IFNR degradation. In vivo monitoring of endosome acidification with
LysosensorTM revealed increased kinetics of endosome acidification in LMP2A and LMP2B-expressing
cells suggesting that LMP2A and LMP2B either function as proton (H+) pumps or modulate the activity
of vacuolar ATPases.
EBV Conference 2008 Guangzhou
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