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Human cystatin C forms an inactive dimer during intracellular trafficking in transfected CHO cells.
[hereditary cerebral hemorrhage with amyloidosis]
To
define
the
cellular
processing
of
human
cystatin
C
as
well
as
to
lay
the
groundwork
for
investigating
its
contribution
to
lcelandic
Hereditary
Cerebral
Hemorrhage
with
Amyloidosis
(
HCHWA
-
I
)
,
we
have
characterized
the
trafficking
,
secretion
,
and
extracellular
fate
of
human
cystatin
C
in
transfected
Chinese
hamster
ovary
(
CHO
)
cells
.
It
is
constitutively
secreted
with
an
intracellular
half
-life
of
72
min
.
Gel
filtration
of
cell
lysates
revealed
the
presence
of
three
cystatin
C
immunoreactive
species
;
an
11
kDa
species
corresponding
to
monomeric
cystatin
C
,
a
33
kDa
complex
that
is
most
likely
dimeric
cystatin
C
and
immunoreactive
material
,
>
or
=
70
kDa
,
whose
composition
is
unknown
.
Intracellular
monomeric
cystatin
C
is
functionally
active
as
a
cysteine
protease
inhibitor
,
while
the
dimer
is
not
.
Medium
from
the
transfected
CHO
cells
contained
only
active
monomeric
cystatin
C
indicating
that
the
cystatin
C
dimer
,
formed
during
intracellular
trafficking
,
is
converted
to
monomer
at
or
before
secretion
.
Cells
in
which
exit
from
the
endoplasmic
reticulum
(
ER
)
was
blocked
with
brefeldin
A
contained
the
33
kDa
species
,
indicating
that
cystatin
C
dimerization
occurs
in
the
ER
.
After
removal
of
brefeldin
A
,
there
was
a
large
increase
in
intracellular
monomer
suggesting
that
dimer
dissociation
occurs
later
in
the
secretion
pathway
,
after
exiting
the
ER
but
prior
to
release
from
the
cell
.
Extracellular
monomeric
cystatin
C
was
found
to
be
internalized
into
lysosomes
where
it
again
dimerized
,
presumably
as
a
consequence
of
the
low
pH
of
late
endosome
/
lysosomes
.
As
a
dimer
,
cystatin
C
would
be
prevented
from
inhibiting
the
lysosomal
cysteine
proteases
.
These
results
reveal
a
novel
mechanism
,
transient
dimerization
,
by
which
cystatin
C
is
inactivated
during
the
early
part
of
its
trafficking
through
the
secretory
pathway
and
then
reactivated
prior
to
secretion
.
Similarly
,
its
uptake
by
the
cell
also
leads
to
its
redimerization
in
the
lysosomal
pathway
.
Diseases
Validation
Diseases presenting
"transfected chinese hamster"
symptom
hereditary cerebral hemorrhage with amyloidosis
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