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RhoA activation by CNFy restores cell-cell adhesion in kindlin-2-deficient keratinocytes.
[kindler syndrome]
Kindlins
are
a
family
of
integrin
adapter
and
cell-matrix
adhesion
proteins
causally
linked
to
human
genetic
disorders
.
Kindlin-
2
is
a
ubiquitously
expressed
protein
with
manifold
functions
and
interactions
.
The
contribution
of
kindlin-
2
to
integrin-based
cell-matrix
adhesions
has
been
extensively
explored
,
while
other
integrin-independent
roles
emerge
.
Because
of
the
early
involvement
of
kindlin-
2
in
development
,
no
viable
animal
models
with
its
constitutional
knockout
are
available
to
study
its
physiological
functions
in
adult
skin
.
Here
,
we
uncovered
a
critical
physiological
role
of
kindlin-
2
in
the
epidermis
by
using
a
skin
-equivalent
model
with
shRNA-mediated
knock-down
of
kindlin-
2
in
keratinocytes
.
Kindlin-
2
-
deficient
keratinocytes
built
stratified
epidermal
layers
,
but
displayed
impaired
dermal-epidermal
and
intra-epidermal
adhesion
and
barrier
function
.
Co
-immunoprecipitation
studies
demonstrated
that
kindlin-
2
interacts
with
both
integrin-
and
cadherin-based
adhesions
.
In
kindlin-
2
-
deficient
keratinocytes
,
reduced
cell-cell
adhesion
was
associated
with
abnormal
cytoplasmic
distribution
of
adherens
junctions
and
desmosomal
proteins
,
which
was
dependent
on
RhoA
activation
.
Direct
activation
of
RhoA
with
recombinant
bacterial
cytotoxic
necrotizing
factor
y
(
CNFy
)
reverted
the
abnormal
phenotype
and
barrier
function
of
kindlin-
2
-
deficient
keratinocytes
and
skin
equivalents
.
These
findings
have
physiological
and
pathological
significance
,
since
kindlin-
2
expression
modulates
the
phenotype
in
Kindler
syndrome
,
a
skin
fragility
disorder
caused
by
kindlin-
1
deficiency
.
Our
results
suggest
that
pharmacological
regulation
of
RhoGTPase
activity
may
represent
a
therapeutic
option
for
skin
fragility
.
