Redox Biology,
Год журнала:
2025,
Номер
unknown, С. 103623 - 103623
Опубликована: Март 1, 2025
Allergic
airway
inflammation
(AAI)
is
a
prevalent
respiratory
disorder
that
affects
vast
number
of
individuals
globally.
There
exists
complex
interplay
among
inflammation,
immune
responses,
and
metabolic
processes,
which
paramount
importance
in
the
pathogenesis
AAI.
Metabolic
dysregulation
protein
translational
modification
(PTM)
are
well-recognized
hallmarks
diseases,
playing
pivotal
roles
onset
progression
numerous
ailments.
However,
role
gut
microbiota
metabolites
development
AAI,
as
well
their
influence
on
PTM
modifications
within
this
disease
context,
have
not
been
thoroughly
explored
investigated
thus
far.
In
AAI
patients,
succinate
was
identified
key
metabolite,
positively
correlated
with
certain
parameters
IgE
levels,
having
good
diagnostic
value.
mice,
bacteria
were
main
source
high
levels.
Mendelian
randomization
showed
risk
factor
for
asthma.
Exogenous
worsened
increasing
resistance
inflammatory
Protein
succinylation
mice
lungs
differed
significantly
from
normal
up-regulated
proteins
pathways.
FMT
alleviated
symptoms
by
reducing
vitro,
promoted
BEAS-2B
cells,
SOD2
succinylated
protein,
K68
site
crucial
its
enzyme
activity
regulation.
Gut
flora-derived
exacerbates
lung
succinylation,
can
reverse
this.
These
findings
offer
new
insights
into
mechanisms
potential
therapeutic
targets.
Cell Reports,
Год журнала:
2024,
Номер
43(7), С. 114381 - 114381
Опубликована: Июнь 25, 2024
Succinate,
a
citric
acid
cycle
intermediate,
serves
important
functions
in
energy
homeostasis
and
metabolic
regulation.
Extracellular
succinate
acts
as
stress
signal
through
receptor
(SUCNR1),
class
A
G
protein-coupled
receptor.
Research
on
signaling
is
hampered
by
the
lack
of
high-resolution
structures
agonist-bound
We
present
cryoelectron
microscopy
(cryo-EM)
SUCNR1-Gi
complexes
bound
to
its
non-metabolite
derivative
cis-epoxysuccinate.
Key
determinants
for
recognition
cis
conformation
include
R2817.39
Y832.64,
while
Y301.39
R993.29
participate
binding
both
loop
2,
F175ECL2
β-hairpin,
forms
hydrogen
bond
with
caps
pocket.
At
receptor-Gi
interface,
agonist
induces
rearrangement
hydrophobic
network
transmembrane
(TM)5
TM6,
leading
TM
TM3
TM7.
These
findings
extend
our
understanding
SUCNR1,
aiding
development
therapeutics
Metformin
is
the
first-line
pharmacotherapy
for
type
2
diabetes
mellitus;
however,
many
patients
respond
poorly
to
this
drug
in
clinical
practice.
The
potential
involvement
of
microbiota-mediated
intestinal
immunity
and
related
signals
metformin
responsiveness
has
not
been
previously
investigated.
In
study,
we
successfully
constructed
a
humanized
mouse
model
by
fecal
transplantation
gut
microbiota
from
metformin-treated
–
responders
non-responders,
reproduced
difference
phenotypes
metformin.
abundance
Bacteroides
thetaiotaomicron,
considered
representative
differential
bacterium
responsiveness,
level
secretory
immunoglobulin
A
(SIgA)
increased
significantly
responder
recipient
mice
following
treatment.
contrast,
no
significant
alterations
B.
thetaiotaomicron
SIgA
were
observed
non-responder
mice.
study
IgA˗/˗
confirmed
that
downregulated
expression
or
deficiency
resulted
non-response
metformin,
meaning
was
unable
improve
dysfunctional
glucose
metabolism
reduce
adipose
tissue
inflammation,
ultimately
leading
systemic
insulin
resistance.
Furthermore,
supplementation
with
succinate,
microbial
product
potentially
reversed
inducing
production
SIgA.
conclusion,
demonstrated
upregulated
SIgA,
which
could
be
regulated
functionally
involved
response
through
its
influence
on
immune
cell-mediated
inflammation
Conversely,
an
inability
regulate
may
result
lack
Succinate
is
a
pivotal
tricarboxylic
acid
cycle
metabolite
but
also
specifically
activates
the
G
i
‐
and
q
‐coupled
succinate
receptor
1
(SUCNR1).
Contradictory
roles
of
succinate‐SUCNR1
signaling
include
reports
about
its
anti‐
or
pro‐inflammatory
effects.
The
link
between
cellular
metabolism
localization‐dependent
SUCNR1
qualifies
as
potential
cause
for
reported
conflicts.
To
systematically
address
this
connection,
we
used
diverse
set
methods,
including
several
bioluminescence
resonance
energy
transfer‐based
biosensors,
dynamic
mass
redistribution
measurements,
second
messenger
kinase
phosphorylation
assays,
calcium
imaging,
metabolic
analyses.
Different
states
were
mimicked
using
glucose
(Glc)
glutamine
(Gln)
available
substrates
to
provoke
differential
endogenous
(SUC)
production.
We
show
that
signaling,
localization,
are
mutually
dependent,
with
showing
distinct
spatial
substrate‐dependent
protein
activation.
found
Gln‐consumption
associated
higher
rate
oxidative
causes
increased
extracellular
SUC
concentrations,
accompanied
by
internalization,
reduced
miniG
recruitment
plasma
membrane,
lower
Ca
2+
signals.
In
Glc,
under
basal
conditions,
stronger
than
activation,
while
opposite
true
upon
stimulation
an
agonist.
addition,
interacts
proteins
in
endosomal
compartments.
THP‐1
cells,
polarized
M2‐like
macrophages,
SUCNR1‐mediated
stimulates
glycolysis,
inhibits
glycolytic
rate.
Our
results
suggest
context
determines
spatially
dependent
which
turn
modulates
homeostasis
mediates
adaptations
changes
concentrations.
Redox Biology,
Год журнала:
2025,
Номер
unknown, С. 103623 - 103623
Опубликована: Март 1, 2025
Allergic
airway
inflammation
(AAI)
is
a
prevalent
respiratory
disorder
that
affects
vast
number
of
individuals
globally.
There
exists
complex
interplay
among
inflammation,
immune
responses,
and
metabolic
processes,
which
paramount
importance
in
the
pathogenesis
AAI.
Metabolic
dysregulation
protein
translational
modification
(PTM)
are
well-recognized
hallmarks
diseases,
playing
pivotal
roles
onset
progression
numerous
ailments.
However,
role
gut
microbiota
metabolites
development
AAI,
as
well
their
influence
on
PTM
modifications
within
this
disease
context,
have
not
been
thoroughly
explored
investigated
thus
far.
In
AAI
patients,
succinate
was
identified
key
metabolite,
positively
correlated
with
certain
parameters
IgE
levels,
having
good
diagnostic
value.
mice,
bacteria
were
main
source
high
levels.
Mendelian
randomization
showed
risk
factor
for
asthma.
Exogenous
worsened
increasing
resistance
inflammatory
Protein
succinylation
mice
lungs
differed
significantly
from
normal
up-regulated
proteins
pathways.
FMT
alleviated
symptoms
by
reducing
vitro,
promoted
BEAS-2B
cells,
SOD2
succinylated
protein,
K68
site
crucial
its
enzyme
activity
regulation.
Gut
flora-derived
exacerbates
lung
succinylation,
can
reverse
this.
These
findings
offer
new
insights
into
mechanisms
potential
therapeutic
targets.
