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Crk adaptors negatively regulate actin polymerization in pedestals formed by enteropathogenic Escherichia coli (EPEC) by binding to Tir effector.
[wiskott-aldrich syndrome]
Infections
by
enteropathogenic
Escherichia
coli
(
EPEC
)
cause
diarrhea
linked
to
high
infant
mortality
in
developing
countries
.
EPEC
adheres
to
epithelial
cells
and
induces
the
formation
of
actin
pedestals
.
Actin
polymerization
is
driven
fundamentally
through
signaling
mediated
by
Tir
bacterial
effector
protein
,
which
inserts
in
the
plasma
membrane
of
the
infected
cell
.
Tir
binds
Nck
adaptor
proteins
,
which
in
turn
recruit
and
activate
N-WASP
,
a
ubiquitous
member
of
the
Wiskott-
Aldrich
syndrome
family
of
proteins
.
N-WASP
activates
the
Arp
2
/
3
complex
to
promote
actin
polymerization
.
Other
proteins
aside
from
components
of
the
Tir-
Nck-
N-WASP
pathway
are
recruited
to
the
pedestals
but
their
functions
are
unknown
.
Here
we
investigate
the
function
of
two
alternatively
spliced
isoforms
of
Crk
adaptors
(
CrkI
/
II
)
and
the
paralog
protein
CrkL
during
pedestal
formation
by
EPEC
.
We
found
that
the
Crk
isoforms
act
as
redundant
inhibitors
of
pedestal
formation
.
The
SH
2
domain
of
CrkII
and
CrkL
binds
to
phosphorylated
tyrosine
474
of
Tir
and
competes
with
Nck
to
bind
Tir
,
preventing
its
recruitment
to
pedestals
and
thereby
inhibiting
actin
polymerization
.
EPEC
infection
induces
phosphorylation
of
the
major
regulatory
tyrosine
in
CrkII
and
CrkL
,
possibly
preventing
the
SH
2
domain
of
these
proteins
from
interacting
with
Tir
.
Phosphorylated
CrkII
and
CrkL
proteins
localize
specifically
to
the
plasma
membrane
in
contact
with
EPEC
.
Our
study
uncovers
a
novel
role
for
Crk
adaptors
at
pedestals
,
opening
a
new
perspective
in
how
these
oncoproteins
regulate
actin
polymerization
.