Regulation of cellular cholesterol distribution via non-vesicular lipid transport at ER-Golgi contact sites
Nature Communications,
Год журнала:
2023,
Номер
14(1)
Опубликована: Сен. 21, 2023
Abstract
Abnormal
distribution
of
cellular
cholesterol
is
associated
with
numerous
diseases,
including
cardiovascular
and
neurodegenerative
diseases.
Regulated
transport
critical
for
maintaining
its
proper
in
the
cell,
yet
underlying
mechanisms
remain
unclear.
Here,
we
show
that
lipid
transfer
proteins,
namely
ORP9,
OSBP,
GRAMD1s/Asters
(GRAMD1a/GRAMD1b/GRAMD1c),
control
non-vesicular
at
points
contact
between
ER
trans-Golgi
network
(TGN),
thereby
distribution.
ORP9
localizes
to
TGN
via
interaction
tandem
α-helices
ORP10/ORP11.
extracts
PI4P
from
prevent
overaccumulation
suppresses
OSBP-mediated
PI4P-driven
Golgi.
By
contrast,
GRAMD1s
excess
Golgi
ER,
preventing
build-up.
Cells
lacking
exhibit
accumulation
Golgi,
which
further
enhanced
by
additional
depletion
major
plasma
membrane.
This
accompanied
chronic
activation
SREBP-2
signalling
pathway.
Our
findings
reveal
importance
regulated
ER-Golgi
contacts
homeostasis.
Язык: Английский
Visualization of accessible cholesterol using a GRAM domain-based biosensor
Nature Communications,
Год журнала:
2023,
Номер
14(1)
Опубликована: Окт. 25, 2023
Cholesterol
is
important
for
membrane
integrity
and
cell
signaling,
dysregulation
of
the
distribution
cellular
cholesterol
associated
with
numerous
diseases,
including
neurodegenerative
disorders.
While
regulated
transport
a
specific
pool
cholesterol,
known
as
"accessible
cholesterol",
contributes
to
maintenance
homeostasis,
tools
monitor
accessible
in
live
cells
remain
limited.
Here,
we
engineer
highly
sensitive
biosensor
by
taking
advantage
cholesterol-sensing
element
(the
GRAM
domain)
an
evolutionarily
conserved
lipid
transfer
protein,
GRAMD1b.
Using
this
biosensor,
which
call
GRAM-W,
successfully
visualize
real
time
many
different
types,
human
keratinocytes
iPSC-derived
neurons,
show
differential
dependencies
on
biosynthesis
uptake
maintaining
levels
cholesterol.
Furthermore,
combine
GRAM-W
dimerization-dependent
fluorescent
protein
(ddFP)
establish
strategy
ultrasensitive
detection
plasma
These
will
allow
us
obtain
insights
into
molecular
mechanisms
regulated.
Язык: Английский
HIV-1 Gag targeting to the plasma membrane reorganizes sphingomyelin-rich and cholesterol-rich lipid domains
Nature Communications,
Год журнала:
2023,
Номер
14(1)
Опубликована: Ноя. 21, 2023
Abstract
Although
the
human
immunodeficiency
virus
type
1
lipid
envelope
has
been
reported
to
be
enriched
with
host
cell
sphingomyelin
and
cholesterol,
molecular
mechanism
of
enrichment
is
not
well
understood.
Viral
Gag
protein
plays
a
central
role
in
budding.
Here,
we
report
interaction
between
lipids
using
different
quantitative
super-resolution
microscopy
techniques
combination
specific
probes
that
bind
endogenous
cholesterol.
Our
results
indicate
inner
leaflet
plasma
membrane
colocalizes
outer
sphingomyelin-rich
domains
cholesterol-rich
domains,
enlarges
strongly
restricts
mobility
domains.
Moreover,
multimerization
induces
close
proximity
curvature-dependent
manner.
study
suggests
binds,
coalesces,
reorganizes
pre-existing
during
assembly.
Язык: Английский
Is reverse cholesterol transport regulated by active cholesterol?
Journal of Lipid Research,
Год журнала:
2023,
Номер
64(6), С. 100385 - 100385
Опубликована: Май 10, 2023
This
review
considers
the
hypothesis
that
a
small
portion
of
plasma
membrane
cholesterol
regulates
reverse
transport
in
coordination
with
overall
cellular
homeostasis.
It
appears
almost
all
is
held
stoichiometric
complexes
bilayer
phospholipids.
The
minor
fraction
exceeds
complexation
capacity
phospholipids
called
active
cholesterol.
has
an
elevated
chemical
activity
and
circulates
among
organelles.
also
moves
down
its
gradient
to
HDL,
facilitated
by
ABCA1,
ABCG1,
SR-BI.
ABCA1
initiates
this
process
perturbing
organization
bilayer,
thereby
priming
for
translocation
apoA-I
form
nascent
HDL.
excess
sterol
activated
itself
follow
ABCG1
similarly
rearranges
sends
additional
while
SR-BI
simply
facilitates
equilibration
between
membranes
proteins.
Active
flows
downhill
cytoplasmic
where
it
serves
both
as
feedback
signal
homeostatic
ER
proteins
substrate
synthesis
mitochondrial
27-hydroxycholesterol
(27HC).
27HC
binds
LXR
promotes
expression
aforementioned
27HC-LXR
activates
competitively
displacing
inhibitor,
unliganded
LXR.
§
Considerable
indirect
evidence
suggests
transport.
Direct
tests
novel
are
proposed.
Язык: Английский
How active cholesterol coordinates cell cholesterol homeostasis: Test of a hypothesis
Progress in Lipid Research,
Год журнала:
2024,
Номер
96, С. 101304 - 101304
Опубликована: Ноя. 1, 2024
How
do
cells
coordinate
the
diverse
elements
that
regulate
their
cholesterol
homeostasis?
Our
model
postulates
membrane
forms
simple
complexes
with
bilayer
phospholipids.
The
phospholipids
in
plasma
are
of
high
affinity;
consequently,
they
fully
complexed
sterol.
This
sets
resting
level
cholesterol.
Cholesterol
excess
stoichiometric
equivalence
point
these
has
chemical
activity;
we
refer
to
it
as
active
It
equilibrates
low
affinity
intracellular
membranes
where
serves
a
negative
feedback
signal
manifold
regulatory
proteins
rein
ongoing
accretion.
We
tested
review
literature
regarding
fourteen
homeostatic
enterocytes.
provided
strong
albeit
indirect
support
for
following
hypothesis.
Active
inhibits
uptake
and
biosynthesis
by
suppressing
both
expression
activity
gene
products
activated
SREBP-2;
namely,
HMGCR,
LDLR
NPC1L1.
also
reduces
free
cell
serving
substrate
its
esterification
ACAT
synthesis
side-chain
oxysterols,
27-hydroxycholesterol
particular.
oxysterols
drive
depletion
promoting
destruction
HMGCR
stimulating
sterol
well
activation
LXR.
latter
fosters
multiple
proteins,
including
four
transporters
which
is
likely
substrate.
By
nulling
cholesterol,
maintains
cellular
at
physiologic
set
point.
Язык: Английский
Estimating the Cholesterol Affinity of Integral Membrane Proteins from Experimental Data
Biochemistry,
Год журнала:
2023,
Номер
63(1), С. 19 - 26
Опубликована: Дек. 15, 2023
The
cholesterol
affinities
of
many
integral
plasma
membrane
proteins
have
been
estimated
by
molecular
computation.
However,
these
values
lack
experimental
confirmation.
We
therefore
developed
a
simple
mathematical
model
to
extract
sterol
affinity
constants
and
stoichiometries
from
published
isotherms
for
the
dependence
activity
such
on
concentration.
binding
curves
are
sigmoidal,
with
strongly
lagged
thresholds
attributable
competition
bilayer
phospholipids.
provided
that
matched
data
using
association
Three
oligomeric
transporters
were
found
bind
without
cooperativity,
dimensionless
35
Kir3.4*
100
both
Kir2
GAT
transporter.
(The
corresponding
ΔG°
−8.8,
−11.4,
−11.4
kJ/mol,
respectively).
These
significantly
lower
than
those
phospholipids,
which
range
∼100
6000.
BK
channel,
nicotinic
acetylcholine
receptor,
M192I
mutant
appear
multiple
molecules
cooperatively
(n
=
2
or
4),
subunit
563,
950,
700,
respectively.
predicts
three
less
avid
approximately
half-saturated
in
their
native
membranes;
hence,
they
sensitive
variations
vivo.
more
would
be
nearly
saturated
method
can
applied
any
protein
other
ligands
there
reasonable
estimates
Язык: Английский
Serum opacity factor normalizes erythrocyte morphology in Scarb1−/− mice in an HDL-free cholesterol-dependent way
Journal of Lipid Research,
Год журнала:
2023,
Номер
64(11), С. 100456 - 100456
Опубликована: Окт. 10, 2023
Compared
to
wild-type
(WT)
mice,
high-density
lipoprotein
(HDL)-receptor-deficient
(Scarb1-/-)
mice
have
higher
plasma
levels
of
free
cholesterol
(FC)-rich
HDL
and
exhibit
multiple
pathologies
associated
with
a
high
mol%
FC
in
ovaries,
platelets,
erythrocytes
which
are
reversed
by
lowering
HDL.
Bacterial
serum
opacity
factor
(SOF)
catalyzes
the
opacification
targeting
quantitatively
converting
neo
(HDL
remnant),
ester-rich
microemulsion,
lipid-free
APOA1.
SOF
delivery
an
adeno-associated
virus
(AAVSOF)
constitutively
lowers
HDL-FC
reverses
female
infertility
Scarb1-/-
HDL-dependent
way.
We
tested
whether
AAVSOF
will
normalize
erythrocyte
morphology
dependent
determined
content
(mol%)
three
groups—WT,
untreated
(control),
receiving
AAVSOF—and
correlated
these
their
respective
HDL-mol%
FC.
Plasma-,
HDL-
tissue-lipid
compositions
were
also
determined.
Plasma-
positively
across
all
groups.
Among
treatment
normalized
reticulocyte
number,
erythrocyte-mol%
Erythrocyte-mol%
both
number
reticulocytes
abnormal
erythrocytes.
reduced
extravascular
tissues
lesser
extent.
spontaneously
transfers
from
cell
membranes.
erythrocyte-FC
normalizes
lipid
composition
reducing
Язык: Английский
A Method For Estimating The Cholesterol Affinity Of Integral Membrane Proteins From Experimental Data
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2023,
Номер
unknown
Опубликована: Окт. 3, 2023
ABSTRACT
The
cholesterol
affinities
of
many
integral
plasma
membrane
proteins
have
been
estimated
by
molecular
computation.
However,
these
values
lack
experimental
confirmation.
We
therefore
developed
a
simple
mathematical
model
to
extract
sterol
affinity
constants
and
stoichiometries
from
published
isotherms
for
the
dependence
activity
such
on
concentration.
binding
curves
are
sigmoidal
with
strongly-lagged
thresholds
attributable
competition
bilayer
phospholipids.
provided
that
matched
data
using
association
Three
oligomeric
transporters
were
found
bind
without
cooperativity
dimensionless
35
Kir3.4*
100
both
Kir2
GAT
transporter.
(The
corresponding
ρG°
-8.8,
-11.4
KJ/mol,
respectively.)
These
significantly
lower
than
those
phospholipids
which
range
∼100
6,000.
BK
channel,
nicotinic
acetylcholine
receptor
M192I
mutant
appear
multiple
molecules
cooperatively
(n
=
2
or
4)
subunit
563,
950
700,
respectively.
predicts
three
less
avid
approximately
half-saturated
in
their
native
membranes;
hence,
sensitive
variations
vivo.
more
would
be
nearly
saturated
method
can
applied
any
protein
other
ligand
there
reasonable
estimates
Язык: Английский