Science Immunology,
Год журнала:
2022,
Номер
7(70)
Опубликована: Апрель 8, 2022
Altered
enteric
microorganisms
in
concert
with
host
genetics
shape
inflammatory
bowel
disease
(IBD)
phenotypes.
However,
insight
is
limited
to
bacteria
and
fungi.
We
found
that
eukaryotic
viruses
bacteriophages
(collectively,
the
virome),
enriched
from
non-IBD,
noninflamed
human
colon
resections,
actively
elicited
atypical
anti-inflammatory
innate
immune
programs.
Conversely,
ulcerative
colitis
or
Crohn's
resection
viromes
provoked
inflammation,
which
was
successfully
dampened
by
non-IBD
viromes.
The
IBD
tissue
virome
perturbed,
including
an
increase
enterovirus
B
species
of
picornaviruses,
not
previously
detected
fecal
studies.
Mice
humanized
were
protected
intestinal
whereas
mice
exhibited
exacerbated
inflammation
a
nucleic
acid
sensing-dependent
fashion.
Furthermore,
there
detrimental
consequences
for
patient-derived
epithelial
cells
bearing
loss-of-function
mutations
within
virus
sensor
MDA5
when
exposed
Our
results
demonstrate
recognition
autonomously
influences
homeostasis
Thus,
perturbations
virome,
altered
ability
sense
due
genetic
variation,
contribute
induction
IBD.
Harnessing
may
offer
therapeutic
biomarker
potential.
Science,
Год журнала:
2020,
Номер
369(6505), С. 823 - 828
Опубликована: Авг. 14, 2020
The
appearance
of
DNA
in
the
cytosol
is
perceived
as
a
danger
signal
that
stimulates
potent
immune
responses
through
cyclic
guanosine
monophosphate-adenosine
monophosphate
synthase
(cGAS).
How
cells
regulate
activity
cGAS
toward
self-DNA
and
guard
against
potentially
damaging
autoinflammatory
fundamental
biological
question.
Here,
we
identify
barrier-to-autointegration
factor
1
(BAF)
natural
opponent
on
genomic
self-DNA.
We
show
BAF
dynamically
outcompetes
for
binding,
hence
prohibiting
formation
DNA-cGAS
complexes
are
essential
enzymatic
activity.
Upon
acute
loss
nuclear
membrane
integrity,
necessary
to
restrict
exposed
DNA.
Our
observations
reveal
safeguard
mechanism,
distinct
from
physical
separation,
by
which
protect
themselves
aberrant
The Journal of Experimental Medicine,
Год журнала:
2020,
Номер
217(11)
Опубликована: Июль 28, 2020
Pathogenic
COPA
variants
cause
a
Mendelian
syndrome
of
immune
dysregulation
with
elevated
type
I
interferon
signaling.
is
subunit
coat
protein
complex
(COPI)
that
mediates
Golgi
to
ER
transport.
Missense
mutations
the
WD40
domain
impair
binding
and
sorting
proteins
targeted
for
retrieval,
but
how
this
causes
disease
remains
unknown.
Given
importance
in
Golgi–ER
transport,
we
speculated
signaling
involves
missorting
STING.
We
show
defect
COPI
transport
ligand-independent
activation
Furthermore,
SURF4
an
adapter
molecule
facilitates
COPA-mediated
retrieval
STING
at
Golgi.
Activated
stimulates
interferon–driven
inflammation
CopaE241K/+
mice
rescued
STING-deficient
animals.
Our
results
demonstrate
maintains
homeostasis
by
regulating
In
addition,
activated
contributes
may
be
new
molecular
target
treating
disease.
