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Loss of Oca2 disrupts the unfolded protein response and increases resistance to endoplasmic reticulum stress in melanocytes.
[oculocutaneous albinism]
Accumulation
of
proteins
in
the
endoplasmic
reticulum
(
ER
)
typically
induces
stress
and
initiates
the
unfolded
protein
response
(
UPR
)
to
facilitate
recovery
.
If
homeostasis
is
not
restored
,
apoptosis
is
induced
.
However
,
adaptation
to
chronic
UPR
activation
can
increase
resistance
to
subsequent
acute
ER
stress
.
We
therefore
investigated
adaptive
mechanisms
in
Oculocutaneous
albinism
type
2
(
Oca
2
)
-
null
melanocytes
where
UPR
signaling
is
arrested
despite
continued
tyrosinase
accumulation
leading
to
resistance
to
the
chemical
ER
stressor
thapsigargin
.
Although
thapsigargin
triggers
UPR
activation
,
instead
of
Perk-mediated
phosphorylation
of
eIF
2
α
,
in
Oca
2
-
null
melanocytes
,
eIF
2
α
was
rapidly
dephosphorylated
upon
treatment
.
Dephosphorylation
was
mediated
by
the
Gadd
34
-
PP
1
α
phosphatase
complex
.
Gadd
34
-
complex
inhibition
blocked
eIF
2
α
dephosphorylation
and
significantly
increased
Oca
2
-
null
melanocyte
sensitivity
to
thapsigargin
.
Thus
,
Oca
2
-
null
melanocytes
adapt
to
acute
ER
stress
by
disruption
of
pro-apoptotic
Perk
signaling
,
which
promotes
cell
survival
.
This
is
the
first
study
to
demonstrate
rapid
eIF
2
α
dephosphorylation
as
an
adaptive
mechanism
to
ER
stress
.