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PROJECT
SUMMARY
Nipah
virus is a newly emerging zoonotic paramyxovirus that has
a broad host tropism and is associated with very high mortality
rate. It predominantly infects endothelial cells and neurons
in vivo, and its cellular receptor has recently been identified
by our lab as EphrinB2.
Ephrin ligands and their Eph receptors
comprise the largest subfamily of the receptor tyrosine kinase
family. Ephrins are divided into two subclasses, the A-subclass,
which are tethered to the cell surface by a GPI anchor, and
the B-subclass, which are transmembrane proteins. Accordingly,
Eph receptors are divided into EphAs and EphBs based on their
ligand binding specificity. The cytoplasmic domains of both
EphrinB ligands and EphB receptors contain phosphorylation
sites. Upon activation, signal is initiated in both the receptor-expressing
and ligand-expressing cells (termed "forward" and
"reverse" signaling, respectively). Eph-Ephrin signaling
pathways have been shown to regulate various biological processes
including axon guidance, vascular development, cell migration,
and tissue-border formation. During viral entry, the G protein
on the surface of Nipah virus binds EphrinB2 with high affinity,
prompting us to think that signaling events might be triggered.
I am currently attempting to identify the possible downstream
signaling pathways and their roles in Nipah virus pathogenesis.
Another part of my work focuses
on the Matrix protein of Nipah. The matrix protein of paramyxoviruses
lines the inner surface of the virion and is known to be involved
in virus budding. Surprisingly, by sequence analysis, we found
two possible nuclear localization signals (NLSs) in the matrix
of Nipah which replicates only in the cytoplasm. So I am trying
to confirm the nuclear localization of matrix. And if this
is true, the next step will be to understand its biological
functions in the nucleus.
References:
Eaton BT, Broder CC, Middleton D,
Wang LF. (2006) Hendra and Nipah viruses: different and dangerous.
Nat Rev Micro 4, 23-35.
Negrete OA, Levroney EL, Aguilar
HC, Bertolotti-Ciarlet A, Nazarian R, Tajyar S, Lee B. (2005)
EphrinB2 is the entry receptor for Nipah virus, an emergent
deadly paramyxovirus. Nature 436: 401-405.
Klas Kullander and Rudiger Klein.
(2002) Mechanisms and functions of Eph and Ephrin signaling.
Nature Reviews Molecular Cell Biology, Vol 3, 475-486.
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