bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Окт. 24, 2024
Abstract
Plasmodium
parasites
undergo
development
and
replication
within
the
hepatocytes
before
infecting
erythrocytes
initiating
clinical
malaria.
Although
type-I
interferons
(IFNs)
are
known
to
hinder
infection
liver,
underlying
mechanisms
remain
unclear.
Here,
we
describe
two
IFN-I-driven
hepatocyte
antimicrobial
programs
controlling
liver-stage
First,
oxidative
defense
by
NADPH
oxidases
2
4
triggers
a
pathway
of
lysosomal
fusion
with
parasitophorous
vacuole
(PV)
help
clear
.
Second,
guanylate-binding
protein
(GBP)
1
disruption
PV
activates
caspase-1
inflammasome,
inducing
pyroptosis
remove
infected
host
cells.
Remarkably,
both
human
mouse
enlist
these
cell-autonomous
immune
eliminate
;
their
pharmacologic
or
genetic
inhibition
led
profound
malarial
susceptibility,
essential
in
vivo
In
addition
identifying
IFN-I-mediated
circuits
hepatocytes,
this
study
extends
our
understanding
how
non-immune
cells
integral
protective
immunity
against
Infectious
diseases
continue
to
claim
many
lives.
Prevention
of
morbidity
and
mortality
from
these
would
benefit
not
just
new
medicines
vaccines
but
also
a
better
understanding
what
constitutes
protective
immunity.
Among
the
major
immune
signals
that
mobilize
host
defense
against
infection
is
interferon-γ
(IFN-γ),
protein
secreted
by
lymphocytes.
Forty
years
ago,
IFN-γ
was
identified
as
macrophage-activating
factor,
and,
in
recent
years,
there
has
been
resurgent
interest
biology
its
role
human
defense.
Here
we
assess
current
IFN-γ,
revisit
designation
an
"interferon,"
weigh
prospects
therapeutic
globally
pervasive
microbial
pathogens.
Advanced Functional Materials,
Год журнала:
2025,
Номер
unknown
Опубликована: Янв. 23, 2025
Abstract
The
catalytic
activity
of
carbon
dots
(CDs)
has
generated
significant
interest
regarding
their
potential
applications
within
the
biomedical
field.
However,
structure‐activity
relationship
CDs
and
pharmacological
mechanisms
in
disease
treatment
have
yet
to
be
comprehensively
elucidated.
In
this
study,
two
distinct
types
exhibiting
superoxide
dismutase
(SOD)‐like
enzymatic
activities
are
synthesized
through
hydrothermal
(Hy‐CDs)
carbonization
(Ca‐CDs)
methods,
utilizing
Honeysuckle
as
common
material
precursor.
Through
comparative
analysis,
surface
group
modifications,
theoretical
calculations,
it
is
determined
that
SOD‐like
primarily
originated
from
stabilizing
influence
amino
on
(•O
2
−
)
intermediate
its
conjugation
π‐system,
facilitating
electron
transfer.
vitro
experiments
demonstrated
Hy‐CDs
effectively
alleviated
cellular
oxidative
stress
inhibited
secretion
pro‐inflammatory
cytokines.
Furthermore,
bioactivity
properties
contribute
pronounced
therapeutic
efficacy
acute
lung
injury
(ALI)
ischemia/reperfusion
(LIRI).
Guided
by
transcriptomic
analysis
Western
blotting,
inhibit
Caspase11/GSDMD‐dependent
non‐classical
pyroptosis
down‐regulating
GBP2
protein
expression,
thereby
contributing
inflammation.
This
study
elucidates
underlying
biological
applications.
Disruption
of
cellular
activities
by
pathogen
virulence
factors
can
trigger
innate
immune
responses.
Interferon-γ
(IFN-γ)-inducible
antimicrobial
factors,
such
as
the
guanylate
binding
proteins
(GBPs),
promote
cell-intrinsic
defense
attacking
intracellular
pathogens
and
inducing
programmed
cell
death.
Working
in
human
macrophages,
we
discovered
that
GBP1
expression
absence
IFN-γ
killed
cells
induced
Golgi
fragmentation.
exposure
improved
macrophage
survival
through
activity
kinase
PIM1.
PIM1
phosphorylated
GBP1,
leading
to
its
sequestration
14-3-3σ,
which
thereby
prevented
membrane
association.
During
Nature Structural & Molecular Biology,
Год журнала:
2024,
Номер
unknown
Опубликована: Окт. 11, 2024
Abstract
Guanylate-binding
proteins
(GBPs)
are
interferon-inducible
guanosine
triphosphate
hydrolases
(GTPases)
mediating
host
defense
against
intracellular
pathogens.
Their
antimicrobial
activity
hinges
on
their
ability
to
self-associate
and
coat
pathogen-associated
compartments
or
cytosolic
bacteria.
Coat
formation
depends
GTPase
but
how
nucleotide
binding
hydrolysis
prime
remains
unclear.
Here,
we
report
the
cryo-electron
microscopy
structure
of
full-length
human
GBP1
dimer
in
its
guanine
nucleotide-bound
state
describe
molecular
ultrastructure
liposomes
bacterial
lipopolysaccharide
membranes.
Conformational
changes
middle
effector
domains
expose
isoprenylated
C
terminus
for
membrane
association.
The
α-helical
form
a
parallel,
crossover
arrangement
essential
position
extended
domain
intercalation
into
layer
gram-negative
Nucleotide
create
oligomeric
scaffolds
with
contractile
abilities
that
promote
extrusion
fragmentation.
Our
data
offer
structural
mechanistic
framework
understanding
functions
immunity.
Current Opinion in Structural Biology,
Год журнала:
2025,
Номер
93, С. 103058 - 103058
Опубликована: Май 14, 2025
Cryo-electron
tomography
is
the
best-suited
imaging
technique
for
visual
proteomics.
Recent
advances
have
increased
number,
quality,
and
resolution
of
tomograms.
However,
object
detection
bottleneck
task
analysis
workflow
because,
so
far,
only
a
few
molecules
can
be
detected
by
computer
methods
pattern
recognition.
This
article
introduces
major
challenges
in
detecting
molecular
complexes
cryo-electron
tomography.
paper
also
identifies
limitations
current
methods.
Finally,
it
describes
approaches
proposed
to
overcome
these
limitations.
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2025,
Номер
unknown
Опубликована: Фев. 15, 2025
Bats
are
asymptomatic
reservoirs
of
several
zoonotic
viruses.
This
may
result
from
long-term
coevolution
between
viruses
and
bats,
that
have
led
to
host
adaptations
contributing
an
effective
balance
strong
antiviral
responses
with
innate
immune
tolerance.
To
better
understand
these
virus-host
interactions,
we
combined
comparative
transcriptomics,
phylogenomics
functional
assays
characterize
the
evolution
bat
factors.
First,
stimulated
type
I
interferon
pathway
in
Myotis
yumanensis
primary
cells
identified
guanylate-binding
protein
5
(GBP5)
as
most
differentially
expressed
interferon-stimulated
gene
(ISG).
Phylogenomic
analyses
showed
GBP5
has
been
under
episodic
positive
selection,
numerous
rapidly
evolving
sites
species-specific
duplications,
suggesting
past
evolutionary
arms
races.
Functional
tests
on
orthologs
ten
species
covering
>60
million
years
Chiroptera
revealed
species-
virus-specific
restrictions
against
RNA
(retrovirus
HIV,
rhabdoviruses
European
lyssavirus
VSV),
which
typical
signatures
viral
epidemics.
Interestingly,
also
observed
a
lineage-specific
loss
prenylation
motif
common
ancestor
Pipistrellus
Eptesicus
associated
different
subcellular
localization
functions.
Resurrection
ancestral
fuscus
rescued
its
localization,
but
not
complete
activities,
additional
determinants
necessary
for
restriction.
Altogether,
our
results
highlight
contribute
specific
immunity
provide
insights
into
effector
GBP5.
is
upon
stimulation
cells.
Bat
evolved
genomic
genetic
diversification,
including
early
stop
codon
leading
truncation
motif.GBP5
diversification
bats
impacts
their
functions.Bat
GBP5s
exhibit
virus-specificity
ability
inhibit
infectivity
particles,
bearing
glycoproteins
retroviral
vesicular
stomatitis
virus
lyssavirus-1.Resurrection
rescues
full
activity.
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2025,
Номер
unknown
Опубликована: Фев. 16, 2025
In
situ
cryo-electron
tomography
(cryo-ET)
has
recently
been
widely
used
in
observing
subcellular
structures
and
macromolecules
their
native
states
at
high
resolution.
One
of
the
reasons
that
it
not
more
adopted
by
cell
biologists
structural
is
difficulties
sample
preparation.
Here
we
present
Sandwich-LIke
Culturing
Kit
(SLICK),
simplifying
procedure
increasing
throughput
for
preparation
cryo-ET
(69
words).
Communications Biology,
Год журнала:
2025,
Номер
8(1)
Опубликована: Фев. 22, 2025
Guanylate-binding
proteins
(GBPs)
are
interferon-inducible
GTPases
that
confer
protective
immunity
against
a
variety
of
intracellular
pathogens.
GBP2
is
one
the
two
highly
inducible
GBPs,
yet
precise
mechanisms
underlying
activation
and
regulation
GBP2,
in
particular
nucleotide-induced
conformational
changes
remain
poorly
understood.
In
this
study,
we
elucidate
structural
plasticity
upon
nucleotide
binding
through
crystallographic
analysis.
By
determining
crystal
structures
G
domain
(GBP2GD)
complex
with
GDP
nucleotide-free
full-length
K51A
mutation
(GBP2K51A),
unveil
distinct
states
adopted
by
nucleotide-binding
pocket
distal
regions
protein.
Comparison
between
GBP2K51A
structure
homologous
reveals
notable
movement
C-terminal
helical
region,
along
domain.
Through
comparative
analysis,
identify
subtle
but
critical
differences
nucleotide-bound
providing
insights
into
molecular
basis
its
dimer-monomer
transition
enzymatic
activity.
These
findings
pave
way
for
future
investigations
aimed
at
elucidating
GBP2's
role
immune
response
open
avenues
exploring
how
unique
functions
GBPs
could
be
leveraged
to
combat
pathogen
invasion.
Using
biophysical
studies,
authors
provide
insight
interferon-induced
guanylate-binding
protein
2.
towards
new
therapeutic
strategies
overcome