Nucleic Acids Research,
Год журнала:
2024,
Номер
52(4), С. 2012 - 2029
Опубликована: Янв. 15, 2024
In
both
prokaryotic
and
eukaryotic
innate
immune
systems,
TIR
domains
function
as
NADases
that
degrade
the
key
metabolite
NAD+
or
generate
signaling
molecules.
Catalytic
activation
of
requires
oligomerization,
but
how
this
is
achieved
varies
in
distinct
systems.
Short
Argonaute
(pAgo)/TIR-APAZ
(SPARTA)
system,
NADase
activity
triggered
upon
guide
RNA-mediated
recognition
invading
DNA
by
an
unknown
mechanism.
Here,
we
describe
cryo-EM
structures
SPARTA
inactive
monomeric
target
DNA-activated
tetrameric
states.
The
structure
reveals
absence
DNA,
a
C-terminal
tail
TIR-APAZ
occupies
nucleic
acid
binding
cleft
formed
pAgo
subunits,
inhibiting
activation.
active
complex,
displaces
induces
conformational
changes
facilitate
SPARTA-SPARTA
dimerization.
Concurrent
release
rotation
one
domain
allow
it
to
form
composite
catalytic
site
with
other
within
dimer,
self-complementary
interface
mediates
cooperative
tetramerization.
Combined,
study
provides
critical
insights
into
structural
architecture
molecular
mechanism
underlying
DNA-dependent
oligomerization
Toll/interleukin-1
receptor
(TIR)
domain
proteins
function
in
cell
death
and
immunity.
In
plants
bacteria,
TIR
domains
are
often
enzymes
that
produce
isomers
of
cyclic
adenosine
5′-diphosphate–ribose
(cADPR)
as
putative
immune
signaling
molecules.
The
identity
functional
conservation
cADPR
isomer
signals
is
unclear.
A
previous
report
found
a
plant
could
cross-activate
the
prokaryotic
Thoeris
TIR–immune
system,
suggesting
TIR-immune
signals.
Here,
we
generate
autoactive
TIRs
test
converse
hypothesis:
Do
also
immunity?
Using
planta
vitro
assays,
find
overlapping
sets
further
clarify
how
activate
system
via
producing
3′cADPR.
This
study
demonstrates
requirements
for
systems
distinct
across
kingdoms
diversity
small-molecule
products.
Nature,
Год журнала:
2024,
Номер
627(8005), С. 847 - 853
Опубликована: Март 13, 2024
Abstract
Plant
nucleotide-binding
leucine-rich
repeat
(NLR)
immune
receptors
with
an
N-terminal
Toll/interleukin-1
receptor
(TIR)
domain
mediate
recognition
of
strain-specific
pathogen
effectors,
typically
via
their
C-terminal
ligand-sensing
domains
1
.
Effector
binding
enables
TIR-encoded
enzymatic
activities
that
are
required
for
TIR–NLR
(TNL)-mediated
immunity
2,3
Many
truncated
TNL
proteins
lack
effector-sensing
but
retain
similar
and
4,5
The
mechanism
underlying
the
activation
these
TIR
remain
unclear.
Here
we
show
substrates
NAD
+
ATP
induces
phase
separation
in
vitro.
A
condensation
occurs
a
protein
expressed
its
native
promoter
response
to
inoculation
planta.
formation
condensates
is
mediated
by
conserved
self-association
interfaces
predicted
intrinsically
disordered
loop
region
TIRs.
Mutations
disrupt
impair
cell
death
activity
proteins.
Our
data
reveal
as
provide
insight
into
substrate-induced
autonomous
signalling
confer
plant
immunity.
Plants
deploy
cell-surface
and
intracellular
receptors
to
detect
pathogen
attack
trigger
innate
immune
responses.
Inside
host
cells,
families
of
nucleotide-binding/leucine-rich
repeat
(NLR)
proteins
serve
as
sensors
or
downstream
mediators
defence
outputs
cell
death,
which
prevent
disease.
Established
genetic
underpinnings
NLR-mediated
immunity
revealed
various
strategies
plants
adopt
combat
rapidly
evolving
microbial
pathogens.
The
molecular
mechanisms
NLR
activation
signal
transmission
components
controlling
execution
were
less
clear.
Here,
we
review
recent
protein
structural
biochemical
insights
plant
sensor
signalling
functions.
When
put
together,
the
data
show
how
different
families,
whether
transducers,
converge
on
nucleotide-based
second
messengers
cellular
calcium
confer
immunity.
Although
pathogen-activated
NLRs
in
engage
plant-specific
machineries
promote
defence,
comparisons
with
mammalian
receptor
counterparts
highlight
some
shared
working
principles
for
across
kingdoms.
Science,
Год журнала:
2025,
Номер
387(6733), С. 510 - 516
Опубликована: Янв. 30, 2025
Caspase
family
proteases
and
Toll/interleukin-1
receptor
(TIR)-domain
proteins
have
central
roles
in
innate
immunity
regulated
cell
death
humans.
We
describe
a
bacterial
immune
system
comprising
both
caspase-like
protease
TIR-domain
protein.
found
that
the
TIR
protein,
once
it
recognizes
phage
invasion,
produces
previously
unknown
signaling
molecule
adenosine
5′-diphosphate-cyclo[N7:1′′]-ribose
(N7-cADPR).
This
specifically
activates
protease,
which
then
indiscriminately
degrades
cellular
to
halt
replication.
The
TIR-caspase
defense
system,
we
denote
as
type
IV
Thoeris,
is
abundant
bacteria
efficiently
protects
against
propagation.
Our
study
highlights
diversity
of
TIR-produced
molecules
demonstrates
by
caspase
an
ancient
mechanism
immunity.