Current Opinion in Structural Biology,
Год журнала:
2023,
Номер
79, С. 102544 - 102544
Опубликована: Фев. 16, 2023
Amino
acid
pools
in
the
cell
are
monitored
by
dedicated
sensors,
whose
structures
now
coming
into
view.
The
lysosomal
Rag
GTPases
central
to
this
pathway,
and
regulation
of
their
GAP
complexes,
FLCN-FNIP
GATOR1,
have
been
worked
out
detail.
For
FLCN-FNIP,
entire
chain
events
from
arginine
transporter
SLC38A9
substrate-specific
mTORC1
activation
has
visualized.
structure
GATOR2
determined,
hinting
at
an
ordering
amino
signaling
across
a
larger
size
scale
than
anticipated.
centerpiece
signaling,
mTORC1,
revealed
recognize
its
substrates
more
nuanced
mechanisms
previous
appreciated.
Beyond
well-studied
GTPase
machinery,
another
sensor/effector
system,
that
PQLC2
C9orf72-containing
CSW
complex,
is
structural
These
developments
hold
promise
for
further
insights
physiology
lysosome-centric
therapeutics.
The Journal of Cell Biology,
Год журнала:
2021,
Номер
220(9)
Опубликована: Авг. 12, 2021
The
eukaryotic
endomembrane
system
consists
of
multiple
interconnected
organelles.
Rab
GTPases
are
organelle-specific
markers
that
give
identity
to
these
membranes
by
recruiting
transport
and
trafficking
proteins.
During
processes
or
along
organelle
maturation,
one
is
replaced
another,
a
process
termed
cascade,
which
requires
at
its
center
Rab-specific
guanine
nucleotide
exchange
factor
(GEF).
endolysosomal
serves
here
as
prime
example
for
cascade.
Along
with
endosomal
the
Rab5
recruits
activates
Rab7-specific
GEF
Mon1-Ccz1,
resulting
in
Rab7
activation
on
endosomes
subsequent
fusion
lysosomes.
In
this
review,
we
focus
current
idea
Mon1-Ccz1
recruitment
autophagic
pathway.
We
compare
identified
principles
other
GTPase
cascades
endomembranes,
highlight
importance
regulation,
evaluate
context
strength
relevance
recent
developments
vitro
analyses
understand
underlying
foundation
biogenesis
maturation.
Physiological Reviews,
Год журнала:
2022,
Номер
102(3), С. 1393 - 1448
Опубликована: Фев. 21, 2022
ER-phagy
(reticulophagy)
defines
the
degradation
of
portions
endoplasmic
reticulum
(ER)
within
lysosomes
or
vacuoles.
It
is
part
self-digestion
(i.e.,
autophagic)
programs
recycling
cytoplasmic
material
and
organelles,
which
rapidly
mobilize
metabolites
in
cells
confronted
with
nutrient
shortage.
Moreover,
selective
clearance
ER
subdomains
participates
control
size
activity
during
stress,
reestablishment
homeostasis
after
stress
resolution,
removal
parts
aberrant
potentially
cytotoxic
has
been
segregated.
relies
on
individual
and/or
concerted
activation
receptors,
peripheral
integral
membrane
proteins
that
share
presence
LC3/Atg8-binding
motifs
their
cytosolic
domains.
involves
physical
separation
from
bulk
network
delivery
to
endolysosomal/vacuolar
catabolic
district.
This
last
step
accomplished
by
a
variety
mechanisms
including
macro-ER-phagy
(in
fragments
are
sequestered
double-membrane
autophagosomes
eventually
fuse
lysosomes/vacuoles),
micro-ER-phagy
directly
engulfed
endosomes/lysosomes/vacuoles),
direct
fusion
ER-derived
vesicles
lysosomes/vacuoles.
dysfunctional
specific
human
diseases,
its
regulators
subverted
pathogens,
highlighting
crucial
role
for
cell
organism
life.
Molecular Metabolism,
Год журнала:
2022,
Номер
60, С. 101481 - 101481
Опубликована: Март 25, 2022
Spatial
compartmentalization
of
metabolic
pathways
within
membrane-separated
organelles
is
key
to
the
ability
eukaryotic
cells
precisely
regulate
their
biochemical
functions.
Membrane-bound
such
as
mitochondria,
endoplasmic
reticulum
(ER)
and
lysosomes
enable
concentration
precursors
optimized
chemical
environments,
greatly
accelerating
efficiency
both
anabolic
catabolic
reactions,
enabling
division
labor
optimal
utilization
resources.
However,
also
poses
a
challenge
because
it
creates
spatial
discontinuities
that
must
be
bridged
for
reaction
cascades
connected
completed.
To
do
so,
employ
different
methods
coordinate
fluxes
occurring
in
organelles,
membrane-localized
transporters
facilitate
regulated
metabolite
exchange
between
mitochondria
lysosomes,
non-vesicular
transport
via
physical
contact
sites
connecting
ER
with
well
localized
regulatory
signaling
processes
coordinately
activity
all
these
organelles.
Science,
Год журнала:
2022,
Номер
377(6612), С. 1290 - 1298
Опубликована: Авг. 25, 2022
Lysosomes
coordinate
cellular
metabolism
and
growth
upon
sensing
of
essential
nutrients,
including
cholesterol.
Through
bioinformatic
analysis
lysosomal
proteomes,
we
identified
cholesterol
signaling
(LYCHOS,
previously
annotated
as
G
protein-coupled
receptor
155),
a
multidomain
transmembrane
protein
that
enables
cholesterol-dependent
activation
the
master
regulator,
kinase
mechanistic
target
rapamycin
complex
1
(mTORC1).
Cholesterol
bound
to
amino-terminal
permease-like
region
LYCHOS,
mutating
this
site
impaired
mTORC1
activation.
At
high
concentrations,
LYCHOS
GATOR1
complex,
guanosine
triphosphatase
(GTPase)-activating
for
Rag
GTPases,
through
conserved
cytoplasm-facing
loop.
By
sequestering
GATOR1,
promotes
cholesterol-
Rag-dependent
recruitment
lysosomes.
Thus,
functions
in
pathway
couples
concentrations
mTORC1-dependent
anabolic
signaling.
Nature Neuroscience,
Год журнала:
2024,
Номер
27(6), С. 1087 - 1102
Опубликована: Апрель 10, 2024
Abstract
In
neurons,
RNA
granules
are
transported
along
the
axon
for
local
translation
away
from
soma.
Recent
studies
indicate
that
some
of
this
transport
involves
hitchhiking
on
lysosome-related
vesicles.
present
study,
we
leveraged
ability
to
prevent
these
vesicles
into
by
knockout
lysosome–kinesin
adaptor
BLOC-one-related
complex
(BORC)
identify
a
subset
axonal
mRNAs
depend
transport.
We
found
BORC
causes
depletion
large
group
mainly
encoding
ribosomal
and
mitochondrial/oxidative
phosphorylation
proteins.
This
results
in
mitochondrial
defects
eventually
leads
degeneration
human
induced
pluripotent
stem
cell
(iPSC)-derived
mouse
neurons.
Pathway
analyses
depleted
revealed
mechanistic
connection
deficiency
with
common
neurodegenerative
disorders.
These
demonstrate
mRNA
is
critical
maintenance
homeostasis
its
failure
degeneration.
