Abstract
The
immunoproteasome
is
a
specialized
type
of
proteasome
involved
in
MHC
class
I
antigen
presentation,
antiviral
adaptive
immunity,
autoimmunity,
and
also
part
broader
response
to
stress.
Whether
the
regulated
by
DNA
stress,
however,
not
known.
We
here
demonstrate
that
mitochondrial
stress
upregulates
presentation
pathway
via
cGAS/STING/type
interferon
signaling
resulting
cell
autonomous
activation
CD8
+
T
cells.
cGAS/STING‐induced
immune
observed
genomic
conserved
epithelial
mesenchymal
cells
mice
men.
In
patients
with
idiopathic
pulmonary
fibrosis,
chronic
aberrant
lung
concurs
T‐cell
diseased
lungs.
Genetic
depletion
specific
inhibitors
counteract
induced
cytotoxic
activation.
Our
data
thus
unravel
cytoplasmic
sensing
cGAS/STING
as
an
activator
This
represents
novel
potential
pathomechanism
for
fibrosis
opens
new
therapeutic
perspectives.
The
influence
of
the
activation
a
cellular
phenotype
termed
senescence
and
it’s
importance
in
ageing
age-related
diseases
is
becoming
more
evident.
In
fact,
there
huge
effort
to
tackle
these
via
therapeutic
drugs
targeting
senescent
cells
named
senolytics.
However,
clearer
understanding
how
activated
it
has
on
specific
types
tissues
needed.
Here,
we
describe
general
triggers
characteristics
senescence.
addition,
different
diseases.
Molecular and Cellular Biology,
Год журнала:
2022,
Номер
42(10)
Опубликована: Сен. 26, 2022
Cellular
senescence
is
a
stable
form
of
cell
cycle
arrest
associated
with
proinflammatory
responses.
Senescent
cells
can
be
cleared
by
the
immune
system
as
part
normal
tissue
homeostasis.
However,
senescent
also
accumulate
in
aged
and
diseased
tissues,
contributing
to
inflammation
disease
progression.
The
mechanisms
mediating
impaired
immune-mediated
clearance
are
poorly
understood.
Here,
we
report
that
upregulate
checkpoint
molecule
PD-L1,
ligand
for
PD-1
on
cells,
which
drives
inactivation.
induction
PD-L1
dependent
program.
Furthermore,
secreted
factors
released
sufficient
nonsenescent
control
mediated
JAK-STAT
pathway.
In
addition,
show
prolongevity
intervention
rapamycin
downregulates
cells.
Last,
found
upregulated
several
tissues
naturally
mice
lungs
idiopathic
pulmonary
fibrosis
patients.
Together,
our
results
aging
upregulation
major
molecule,
PD-L1.
Targeting
may
offer
new
therapeutic
opportunities
treating
age-associated
diseases.
Nature,
Год журнала:
2024,
Номер
625(7995), С. 585 - 592
Опубликована: Янв. 10, 2024
Abstract
Oncogene-induced
replication
stress
generates
endogenous
DNA
damage
that
activates
cGAS–STING-mediated
signalling
and
tumour
suppression
1–3
.
However,
the
precise
mechanism
of
cGAS
activation
by
remains
enigmatic,
particularly
given
high-affinity
histone
acidic
patch
(AP)
binding
constitutively
inhibits
sterically
hindering
its
double-stranded
(dsDNA)
4–10
Here
we
report
double-strand
break
sensor
MRE11
suppresses
mammary
tumorigenesis
through
a
pivotal
role
in
regulating
activation.
We
demonstrate
MRE11–RAD50–NBN
complex
to
nucleosome
fragments
is
necessary
displace
from
acidic-patch-mediated
sequestration,
which
enables
mobilization
dsDNA.
therefore
essential
for
response
oncogenic
stress,
cytosolic
dsDNA
ionizing
radiation.
Furthermore,
MRE11-dependent
promotes
ZBP1–RIPK3–MLKL-mediated
necroptosis,
suppress
proliferation
breast
tumorigenesis.
Notably,
downregulation
ZBP1
human
triple-negative
cancer
associated
with
increased
genome
instability,
immune
poor
patient
prognosis.
These
findings
establish
as
crucial
mediator
links
activation,
resulting
ZBP1-dependent
necroptosis.
Nature Structural & Molecular Biology,
Год журнала:
2022,
Номер
29(7), С. 639 - 652
Опубликована: Июнь 30, 2022
Abstract
Oxidative
stress
is
a
primary
cause
of
cellular
senescence
and
contributes
to
the
etiology
numerous
human
diseases.
damage
telomeric
DNA
has
been
proposed
premature
by
accelerating
telomere
shortening.
Here,
we
tested
this
model
directly
using
precision
chemoptogenetic
tool
produce
common
lesion
8-oxo-guanine
(8oxoG)
exclusively
at
telomeres
in
fibroblasts
epithelial
cells.
A
single
induction
8oxoG
sufficient
trigger
multiple
hallmarks
p53-dependent
senescence.
Telomeric
activates
ATM
ATR
signaling,
enriches
for
markers
dysfunction
replicating,
but
not
quiescent
Acute
production
fails
shorten
telomeres,
rather
generates
fragile
sites
mitotic
synthesis
indicative
impaired
replication.
Based
on
our
results,
propose
that
oxidative
promotes
rapid
producing
base
lesions
drive
replication-dependent
fragility
absence
shortening
shelterin
loss.
