PLoS ONE,
Journal Year:
2025,
Volume and Issue:
20(2), P. e0319216 - e0319216
Published: Feb. 25, 2025
Drugs
targeting
the
ER-resident
innate
immune
receptor
Stimulator
of
Interferon
Genes
(STING)
are
in
development
for
treatments
cancer
and
inflammatory
diseases.
Accurate
determination
STING
levels
normal
disease
tissue
is
an
essential
component
modeling
pharmacology
drug-target
disposition.
Using
metabolic
labeling
with
deuterium
oxide
paired
high
resolution
mass
spectrometry,
we
report
protein
fractional
synthesis
rates
turnover
wild-type
(C57BL/6)
inflamed
mice
carrying
Trex1
D18N
mutation
(Trex1
)
as
a
STING-dependent
model
human
Acardi-Goutiéres
syndrome.
Remarkably,
half-life
specific
shortest
4
days
colon
lymph
node
longest
24
skeletal
muscle.
Despite
relative
increase
abundance
mouse,
overall
kinetics
degradation
resynthesis
was
similar
between
WT
mice.
The
extent
interferon
stimulated
gene
transcription,
hallmark
SLE
linked
pathophysiology,
correlates
extend
increased
tissues
appears
inversely
proportional
to
rate
STING.
Understanding
STING’s
provides
valuable
quantitative
drug
pharmacology,
dose
frequency
directed
therapies.
Cell,
Journal Year:
2024,
Volume and Issue:
187(15), P. 4043 - 4060.e30
Published: June 14, 2024
Inflammation-induced
neurodegeneration
is
a
defining
feature
of
multiple
sclerosis
(MS),
yet
the
underlying
mechanisms
remain
unclear.
By
dissecting
neuronal
inflammatory
stress
response,
we
discovered
that
neurons
in
MS
and
its
mouse
model
induce
stimulator
interferon
genes
(STING).
However,
activation
STING
requires
detachment
from
stromal
interaction
molecule
1
(STIM1),
process
triggered
by
glutamate
excitotoxicity.
This
initiates
non-canonical
signaling,
which
leads
to
autophagic
degradation
glutathione
peroxidase
4
(GPX4),
essential
for
redox
homeostasis
thereby
inducing
ferroptosis.
Both
genetic
pharmacological
interventions
target
protect
against
inflammation-induced
neurodegeneration.
Our
findings
position
as
central
regulator
detrimental
integrating
inflammation
with
signaling
cause
cell
death,
present
it
tractable
treating
MS.
Science Immunology,
Journal Year:
2024,
Volume and Issue:
9(97)
Published: July 5, 2024
The
past
20
years
have
seen
the
definition
of
human
monogenic
disorders
and
their
autoimmune
phenocopies
underlying
either
defective
or
enhanced
type
I
interferon
(IFN)
activity.
These
delineate
impact
IFNs
in
natural
conditions
demonstrate
that
only
a
narrow
window
IFN
activity
is
beneficial.
Insufficient
predisposes
humans
to
life-threatening
viral
diseases
(albeit
unexpectedly
few)
with
central
role
immunity
respiratory
cerebral
infection.
Excessive
IFN,
perhaps
counterintuitively,
appears
underlie
greater
number
autoinflammatory
and/or
known
as
interferonopathies,
whose
study
has
revealed
multiple
molecular
programs
involved
induction
signaling.
observations
suggest
manipulation
within
physiological
range
may
be
clinically
relevant
for
prevention
treatment
inflammatory
diseases.
Neurotherapeutics,
Journal Year:
2024,
Volume and Issue:
21(4), P. e00368 - e00368
Published: April 30, 2024
In
the
context
of
stroke
and
revascularization
therapy,
brain
ischemia-reperfusion
injury
is
a
significant
challenge
that
leads
to
oxidative
stress
inflammation.
Central
cell's
intrinsic
immunity
cGAS-STING
pathway,
which
typically
activated
by
unusual
DNA
structures.
The
involvement
oxidized
mitochondrial
(ox-mtDNA)-an
byproduct-in
this
type
neurological
damage
has
not
been
fully
explored.
This
study
among
first
examine
effect
ox-mtDNA
on
innate
neurons
following
injury.
Using
rat
model
transient
middle
cerebral
artery
occlusion
cellular
oxygen-glucose
deprivation/reoxygenation,
we
have
discovered
activates
pathway
in
neurons.
Importantly,
pharmacologically
limiting
release
into
cytoplasm
reduces
inflammation
improves
functions.
Our
findings
suggest
targeting
may
be
valuable
strategy
attenuate
therapy
for
acute
ischemic
stroke.
Nature Communications,
Journal Year:
2024,
Volume and Issue:
15(1)
Published: March 29, 2024
Abstract
The
cGAS-STING
pathway
plays
a
crucial
role
in
anti-tumoral
responses
by
activating
inflammation
and
reprogramming
the
tumour
microenvironment.
Upon
activation,
STING
traffics
from
endoplasmic
reticulum
(ER)
to
Golgi,
allowing
signalling
complex
assembly
induction
of
interferon
inflammatory
cytokines.
Here
we
report
that
cGAMP
stimulation
leads
transient
decline
ER
cholesterol
levels,
mediated
Sterol
O-Acyltransferase
1-dependent
esterification.
This
facilitates
membrane
curvature
trafficking
Golgi.
Notably,
identify
two
cholesterol-binding
motifs
confirm
their
contribution
ER-retention
STING.
Consequently,
depletion
intracellular
levels
enhances
activation
upon
stimulation.
In
preclinical
model,
intratumorally
administered
therapy
potentiated
STING-dependent
responses,
which,
combination
with
anti-PD-1
antibodies,
promoted
remission.
Collectively,
demonstrate
sets
threshold
for
through
propose
this
could
be
exploited
cancer
immunotherapy.
International Journal of Molecular Sciences,
Journal Year:
2024,
Volume and Issue:
25(3), P. 1828 - 1828
Published: Feb. 2, 2024
Pattern
recognition
receptors
(PRRs)
recognize
danger
signals
such
as
PAMPs/MAMPs
and
DAMPs
to
initiate
a
protective
immune
response.
TLRs,
NLRs,
CLRs,
RLRs
are
well-characterized
PRRs
of
the
host
system.
cGLRs
have
been
recently
identified
PRRs.
In
humans,
cGAS/STING
signaling
pathway
is
part
cGLRs.
cGAS
recognizes
cytosolic
dsDNA
PAMP
or
DAMP
STING-dependent
response
comprising
type
1
IFN
release,
NF-κB
activation,
autophagy,
cellular
senescence.
The
present
article
discusses
emergence
critical
how
they
regulate
responses.
We
examined
role
signaling,
well-studied
cGLR
system,
in
activation
following
sections
discuss
dysregulation
disease
cross-talk
with
other
maintains
homeostasis.
This
understanding
will
lead
design
better
vaccines
immunotherapeutics
for
various
diseases,
including
infections,
autoimmunity,
cancers.
