Cell Reports,
Год журнала:
2024,
Номер
43(8), С. 114618 - 114618
Опубликована: Авг. 1, 2024
Adar
null
mutant
mouse
embryos
die
with
aberrant
double-stranded
RNA
(dsRNA)-driven
interferon
induction,
and
Mavs
double
mutants,
in
which
induction
is
prevented,
soon
after
birth.
Protein
kinase
R
(Pkr)
aberrantly
activated
pup
intestines
before
death,
intestinal
crypt
cells
die,
villi
are
lost.
Eifak2
triple
mice
rescue
all
defects
have
long-term
survival.
Adenosine
deaminase
acting
on
1
(ADAR1)
PKR
co-immunoprecipitate
from
cells,
suggesting
inhibition
by
direct
interaction.
AlphaFold
studies
an
inhibitory
dsRNA
binding
domain
(dsRBD)-kinase
interaction
ADAR1
dsRBD3-PKR
provide
a
testable
model
of
the
inhibition.
Wild-type
or
editing-inactive
human
expressed
A549
inhibits
activation
endogenous
PKR.
required
for,
but
not
sufficient
Mutating
contact
prevents
co-immunoprecipitation,
activity,
co-localization
cells.
Cell Reports,
Год журнала:
2021,
Номер
37(3), С. 109858 - 109858
Опубликована: Окт. 1, 2021
Cell
death
provides
host
defense
and
maintains
homeostasis.
Zα-containing
molecules
are
essential
for
these
processes.
Z-DNA
binding
protein
1
(ZBP1)
activates
inflammatory
cell
death,
PANoptosis,
whereas
adenosine
deaminase
acting
on
RNA
(ADAR1)
serves
as
an
editor
to
maintain
Here,
we
identify
characterize
ADAR1's
interaction
with
ZBP1,
defining
its
role
in
regulation
tumorigenesis.
Combining
interferons
(IFNs)
nuclear
export
inhibitors
(NEIs)
ZBP1-dependent
PANoptosis.
ADAR1
suppresses
this
PANoptosis
by
interacting
the
Zα2
domain
of
ZBP1
limit
RIPK3
interactions.
Adar1
Nature,
Год журнала:
2022,
Номер
607(7920), С. 776 - 783
Опубликована: Июль 20, 2022
Mutations
of
the
ADAR1
gene
encoding
an
RNA
deaminase
cause
severe
diseases
associated
with
chronic
activation
type
I
interferon
(IFN)
responses,
including
Aicardi-Goutières
syndrome
and
bilateral
striatal
necrosis1-3.
The
IFN-inducible
p150
isoform
contains
a
Zα
domain
that
recognizes
alternative
left-handed
double-helix
structure,
termed
Z-RNA4,5.
Hemizygous
mutations
in
IFN-mediated
pathologies
humans2,3
mice6-8;
however,
it
remains
unclear
how
interaction
Z-RNA
prevents
IFN
activation.
Here
we
show
Z-DNA-binding
protein
1
(ZBP1),
only
other
mammals
known
to
harbour
domains9,
promotes
fatal
pathology
mice
impaired
function.
ZBP1
deficiency
or
mutation
its
domains
reduced
expression
IFN-stimulated
genes
largely
prevented
early
postnatal
lethality
hemizygous
mutated
(Adar1mZα/-
mice).
Adar1mZα/-
showed
upregulation
editing
endogenous
retroelement-derived
complementary
reads,
which
represent
likely
source
Z-RNAs
activating
ZBP1.
Notably,
promoted
manner
independent
RIPK1,
RIPK3,
MLKL-mediated
necroptosis
caspase-8-dependent
apoptosis,
suggesting
novel
mechanism
action.
Thus,
Z-RNA-dependent
pathogenic
responses
by
ZBP1,
could
contribute
interferonopathies
caused
mutations.
Journal of Hematology & Oncology,
Год журнала:
2023,
Номер
16(1)
Опубликована: Фев. 8, 2023
RIG-I-like
receptors
(RLRs)
are
intracellular
pattern
recognition
that
detect
viral
or
bacterial
infection
and
induce
host
innate
immune
responses.
The
RLRs
family
comprises
retinoic
acid-inducible
gene
1
(RIG-I),
melanoma
differentiation-associated
5
(MDA5)
laboratory
of
genetics
physiology
2
(LGP2)
have
distinctive
features.
These
not
only
recognize
RNA
intermediates
from
viruses
bacteria,
but
also
interact
with
endogenous
such
as
the
mislocalized
mitochondrial
RNA,
aberrantly
reactivated
repetitive
transposable
elements
in
human
genome.
Evasion
RLRs-mediated
response
may
lead
to
sustained
infection,
defective
immunity
carcinogenesis.
Therapeutic
targeting
provoke
anti-infection
effects,
anticancer
sensitize
"immune-cold"
tumors
checkpoint
blockade.
In
this
review,
we
summarize
current
knowledge
signaling
discuss
rationale
for
therapeutic
cancer.
We
describe
how
can
be
activated
by
synthetic
oncolytic
viruses,
mimicry
radio-chemotherapy,
agonists
systemically
delivered
vivo.
integration
agonism
interference
CAR-T
cells
provides
new
dimensions
complement
cancer
immunotherapy.
Moreover,
update
progress
recent
clinical
trials
therapy
involving
activation
modulation.
Further
studies
mechanisms
underlying
will
shed
light
on
development
therapeutics.
Manipulation
represents
an
opportunity
clinically
relevant
therapy.
Addressing
challenges
field
help
develop
future
generations
Trends in Genetics,
Год журнала:
2023,
Номер
39(2), С. 109 - 124
Опубликована: Янв. 3, 2023
In
addition
to
the
canonical
right-handed
double
helix,
other
DNA
structures,
termed
'non-B
DNA',
can
form
in
genomes
across
tree
of
life.
Non-B
regulates
multiple
cellular
processes,
including
replication
and
transcription,
yet
its
presence
is
associated
with
elevated
mutagenicity
genome
instability.
These
discordant
roles
fuel
enormous
potential
non-B
drive
genomic
phenotypic
evolution.
Here
we
discuss
recent
studies
establishing
structures
as
novel
functional
elements
subject
natural
selection,
affecting
evolution
transposable
(TEs),
specifying
centromeres.
By
highlighting
contributions
repeated
adaptation
changing
environments,
conclude
that
evolutionary
analyses
should
include
a
perspective
not
only
sequence,
but
also
structure.
