 |
|
Title
|
|
Latent membrane protein 2A of Epstein-Barr virus binds WW domain E3 protein-ubiquitin ligases that ubiquitinate B-cell tyrosine kinases.
|
|
|
Authors
|
|
G.Winberg,
L.Matskova,
F.Chen,
P.Plant,
D.Rotin,
G.Gish,
R.Ingham,
I.Ernberg,
T.Pawson.
|
|
|
Ref.
|
|
Mol Cell Biol, 2000,
20,
8526-8535.
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
The latent membrane protein (LMP) 2A of Epstein-Barr virus (EBV) is implicated
in the maintenance of viral latency and appears to function in part by
inhibiting B-cell receptor (BCR) signaling. The N-terminal cytoplasmic region of
LMP2A has multiple tyrosine residues that upon phosphorylation bind the SH2
domains of the Syk tyrosine kinase and the Src family kinase Lyn. The LMP2A
N-terminal region also has two conserved PPPPY motifs. Here we show that the
PPPPY motifs of LMP2A bind multiple WW domains of E3 protein-ubiquitin ligases
of the Nedd4 family, including AIP4 and KIAA0439, and demonstrate that AIP4 and
KIAA0439 form physiological complexes with LMP2A in EBV-positive B cells. In
addition to a C2 domain and four WW domains, these proteins have a C-terminal
Hect catalytic domain implicated in the ubiquitination of target proteins. LMP2A
enhances Lyn and Syk ubiquitination in vivo in a fashion that depends on the
activity of Nedd4 family members and correlates with destabilization of the Lyn
tyrosine kinase. These results suggest that LMP2A serves as a molecular scaffold
to recruit both B-cell tyrosine kinases and C2/WW/Hect domain E3
protein-ubiquitin ligases. This may promote Lyn and Syk ubiquitination in a
fashion that contributes to a block in B-cell signaling. LMP2A may potentiate a
normal mechanism by which Nedd4 family E3 enzymes regulate B-cell signaling.
|
|
|
|