Current Opinion in Cell Biology,
Год журнала:
2024,
Номер
89, С. 102395 - 102395
Опубликована: Июль 5, 2024
The
exocytic
and
endocytic
intracellular
trafficking
pathways
in
innate
immune
cells
are
known
for
mediating
the
secretion
of
key
inflammatory
mediators
or
internalization
growth
factors,
nutrients,
antigens,
cell
debris,
pathogens
even
therapeutics,
respectively.
Inside
cells,
these
intertwined
as
an
elaborate
network
that
supports
regulation
functions.
Endosomal
membranes
host
dynamic
platforms
molecular
complexes
control
signaling
responses.
High
content
screens,
coupled
with
elegant
microscopy
across
scale
resolving
to
tracking
live
cellular
organelles,
have
been
employed
generate
studies
highlighted
here.
With
a
focus
on
deactivation
STING,
scaffolding
by
SLC15A4/TASL
macropinosome
shrinkage
via
chloride
channel
protein
TMEM206,
new
identifying
molecules,
interactions
mechanisms
throughout
endosomal
pathways.
Frontiers in Immunology,
Год журнала:
2025,
Номер
16
Опубликована: Фев. 20, 2025
Systemic
lupus
erythematosus
(SLE)
predominately
affects
women
with
a
ratio
of
females-to-males
about
9:1.
The
complement
sex
chromosomes
may
play
and
important
role
in
the
mechanism
bias.
Previous
work
has
shown
that
men
Klinefleter's
syndrome
(47,XXY)
as
well
47,XXX
are
found
excess
among
SLE
patients
Sjogren's
disease,
systemic
sclerosis
idiopathic
inflammatory
myositis.
cells
more
than
one
X
chromosome,
all
but
is
inactivated.
However,
chromosome
inactivation,
mediated
by
long
noncoding
RNA
X-inactive
specific
transcript,
or
XIST,
not
complete
approximately
10%
genes
non-recombining
region
escaping
inactivation.
In
TLR7
signaling
pathway,
both
TLR
adaptor
interacting
endolysosomal
SLC15A4
(TASL)
escape
Comparing
male
female
immune
cells,
there
increased
related
to
expression
these
chromosome.
Cells
also
express
while
do
not.
source
ligand
for
TLR7,
been
increase
signaling.
Thus,
we
propose
mechanisms
operating
act
mutual
way
mediate
an
dose
effect
bias
autoimmune
disease.
Signal Transduction and Targeted Therapy,
Год журнала:
2024,
Номер
9(1)
Опубликована: Окт. 9, 2024
Interferon
Regulatory
Factors
(IRFs),
a
family
of
transcription
factors,
profoundly
influence
the
immune
system,
impacting
both
physiological
and
pathological
processes.
This
review
explores
diverse
functions
nine
mammalian
IRF
members,
each
featuring
conserved
domains
essential
for
interactions
with
other
factors
cofactors.
These
allow
IRFs
to
modulate
broad
spectrum
processes,
encompassing
host
defense,
response,
cell
development.
Conversely,
their
pivotal
role
in
regulation
implicates
them
pathophysiology
various
diseases,
such
as
infectious
autoimmune
disorders,
metabolic
cancers.
In
this
context,
display
dichotomous
nature,
functioning
tumor
suppressors
promoters,
contingent
upon
specific
disease
milieu.
Post-translational
modifications
IRFs,
including
phosphorylation
ubiquitination,
play
crucial
modulating
function,
stability,
activation.
As
prospective
biomarkers
therapeutic
targets,
present
promising
opportunities
intervention.
Further
research
is
needed
elucidate
precise
mechanisms
governing
regulation,
potentially
pioneering
innovative
strategies,
particularly
cancer
treatment,
where
equilibrium
activities
paramount
importance.
Nature Communications,
Год журнала:
2025,
Номер
16(1)
Опубликована: Янв. 24, 2025
Abstract
Endosomal
nucleic
acid
sensing
by
Toll-like
receptors
(TLRs)
is
central
to
antimicrobial
immunity
and
several
autoimmune
conditions
such
as
systemic
lupus
erythematosus
(SLE).
The
innate
immune
adaptor
TASL
mediates,
via
the
interaction
with
SLC15A4,
activation
of
IRF5
downstream
human
TLR7,
TLR8
TLR9,
but
pathophysiological
functions
this
axis
remain
unexplored.
Here
we
show
that
SLC15A4
deficiency
results
in
a
selective
block
TLR7/9-induced
activation,
while
loss
leads
strong
incomplete
impairment,
which
depends
on
cell
type
TLR
engaged.
This
residual
activity
ascribed
previously
uncharacterized
paralogue,
Gm6377
,
named
here
TASL2.
Double
knockout
TASL2
(TASL
DKO
)
phenocopies
SLC15A4-deficient
feeble
mice
showing
comparable
impairment
humoral
responses.
Consequently,
fail
control
chronic
LCMV
infection,
being
protected
pristane-induced
SLE
disease
model.
Our
study
thus
demonstrates
critical
role
TASL/TASL2
for
TLR7/9-driven
inflammatory
responses,
further
supporting
therapeutic
potential
targeting
complex
related
diseases.
Bioelectricity,
Год журнала:
2025,
Номер
7(1), С. 29 - 57
Опубликована: Март 1, 2025
In
recent
years,
there
has
been
a
growing
interest
in
lysosomal
ion
channels
and
transporters
due
to
their
critical
role
maintaining
function
involvement
variety
of
diseases,
particularly
storage
cancer,
neurodegenerative
disorders.
Recent
advancements
research
techniques,
including
manual
automated
patch
clamp
(APC)
electrophysiology,
solid-supported
membrane-based
electrophysiology
(SSME),
fluorescence-based
imaging,
have
further
enhanced
our
ability
investigate
both
physiological
pathological
conditions,
spurring
drug
discovery
efforts.
Several
pharmaceutical
companies
are
now
developing
therapies
aimed
at
modulating
these
improve
disease.
Small
molecules
targeting
like
transient
receptor
potential
mucolipin
(TRPML)
1
TMEM175,
as
well
drugs
pH,
currently
preclinical
clinical
development.
This
review
provides
an
overview
the
health
disease,
highlights
cutting-edge
techniques
used
study
them,
discusses
therapeutic
treatment
various
diseases.
Furthermore,
addition
summarizing
discoveries,
we
contribute
novel
functional
data
on
cystinosin,
TRPML1,
two-pore
channel
2
(TPC2),
utilizing
SSME
APC
approaches.
Nature Communications,
Год журнала:
2023,
Номер
14(1)
Опубликована: Окт. 20, 2023
Dysregulation
of
pathogen-recognition
pathways
the
innate
immune
system
is
associated
with
multiple
autoimmune
disorders.
Due
to
intricacies
molecular
network
involved,
identification
pathway-
and
disease-specific
therapeutics
has
been
challenging.
Using
a
phenotypic
assay
monitoring
degradation
adapter
TASL,
we
identify
feeblin,
chemical
entity
which
inhibits
nucleic
acid-sensing
TLR7/8
pathway
activating
IRF5
by
disrupting
SLC15A4-TASL
module.
A
high-resolution
cryo-EM
structure
feeblin
SLC15A4
reveals
that
inhibitor
binds
lysosomal
outward-open
conformation
incompatible
TASL
binding
on
cytoplasmic
side,
leading
TASL.
This
mechanism
action
exploits
conformational
switch
converts
target-binding
event
into
proteostatic
regulation
effector
protein
interrupting
TLR7/8-IRF5
signaling
preventing
downstream
proinflammatory
responses.
Considering
all
components
involved
have
genetically
systemic
lupus
erythematosus
blocks
responses
in
disease-relevant
human
cells
from
patients,
study
represents
proof-of-concept
for
development
against
this
disease.
Cellular and Molecular Life Sciences,
Год журнала:
2024,
Номер
81(1)
Опубликована: Март 1, 2024
Abstract
Toll-like
receptors
(TLRs),
especially
TLR7,
play
an
important
role
in
systemic
lupus
erythematosus
(SLE)
pathogenesis.
However,
the
regulatory
mechanism
underlying
abnormal
activation
of
TLR
pathways
patients
with
SLE
has
not
been
elucidated.
Notably,
accumulating
evidence
indicates
that
myeloid-derived
suppressor
cells
(MDSCs)
are
regulators
inflammation
and
autoimmune
diseases.
Compared
healthy
control
subjects,
have
a
greater
proportion
MDSCs
among
peripheral
blood
mononuclear
(PBMCs);
however,
effect
on
TLR7
pathway
determined.
In
present
study,
significantly
promoted
macrophages
dendritic
(DCs),
exacerbating
imiquimod-induced
model.
RNA-sequencing
analysis
revealed
significant
overexpression
S100
calcium-binding
protein
A8
(S100A8)
S100A9
from
diseased
MRL/
lpr
mice.
vitro
vivo
studies
demonstrated
S100A8/9
effectively
deficiency
reversed
promoting
lupus.
Mechanistically,
MDSC-derived
upregulated
interferon
gamma
(IFN-γ)
secretion
by
IFN-γ
subsequently
autocrine
manner.
Taken
together,
these
findings
suggest
promote
pathogenesis
through
S100A8/9-IFN-γ
axis.
Our
study
identified
target
for
therapy.
The
innate
immune
system
relies
on
a
network
of
signaling
proteins
classified
by
shared
domains,
which
serve
as
functional
units
that
orchestrate
inflammatory
and
host
defensive
activities.
Within
type
I
interferon
(IFN)
responses,
the
stimulator
genes
protein
(STING),
mitochondrial
antiviral‐signaling
(MAVS),
Toll‐IL‐1
receptor‐resistance
domain‐containing
adapter‐inducing
interferon‐β
(TRIF),
Toll‐like
receptor
adapter
interacting
with
SLC15A4
lysosome
(TASL),
insulin
tyrosine
kinase
substrate
53
kDa
(IRSp53),
GEM
(GMIP)
utilize
conserved
pLxIS
motif
to
recruit
IRF
family
transcription
factors.
Notably,
functions
within
larger
unit,
is
referred
here
an
Activator
Interferon
Expression
via
(ARIES)
domain.
ARIES
domains
consist
adjacent
activation
motifs
together
drive
IFN
responses.
This
review
explores
how
promote
responses
distinct
mechanisms,
localization,
regulation
metabolic
shifts,
underscoring
their
evolutionary
conservation
critical
role
in
defense.
Nature Communications,
Год журнала:
2023,
Номер
14(1)
Опубликована: Окт. 20, 2023
Toll-like
receptors
(TLRs)
are
a
class
of
proteins
that
play
critical
roles
in
recognizing
pathogens
and
initiating
innate
immune
responses.
TASL,
recently
identified
adaptor
protein
for
endolysosomal
TLR7/8/9
signaling,
is
recruited
by
the
lysosomal
proton-coupled
amino-acid
transporter
SLC15A4,
then
activates
IRF5,
which
turn
triggers
transcription
type
I
interferons
cytokines.
Here,
we
report
three
cryo-electron
microscopy
(cryo-EM)
structures
human
SLC15A4
apo
monomeric
dimeric
state
as
TASL-bound
complex.
The
forms
an
outward-facing
conformation,
with
form
showing
extensive
interface
involving
four
cholesterol
molecules.
structure
complex
reveals
unprecedented
interaction
mode
solute
carriers.
During
recruitment
undergoes
conformational
change
from
outward-facing,
lumen-exposed
to
inward-facing
binding
pocket,
allowing
N-terminal
helix
TASL
be
inserted
into.
Our
findings
provide
insights
into
molecular
basis
regulatory
switch
carrier
offers
important
framework
structure-guided
drug
discovery
targeting
SLC15A4-TASL-related
autoimmune
diseases.
Cell Reports,
Год журнала:
2024,
Номер
43(2), С. 113795 - 113795
Опубликована: Фев. 1, 2024
Activation
of
endosomal
Toll-like
receptor
(TLR)
7,
TLR9,
and
TLR11/12
is
a
key
event
in
the
resistance
against
parasite
Toxoplasma
gondii.
Endosomal
TLR
engagement
leads
to
expression
interleukin
(IL)-12
via
myddosome,
protein
complex
containing
MyD88
IL-1
receptor-associated
kinase
(IRAK)
4
addition
IRAK1
or
IRAK2.
In
murine
macrophages,
IRAK2
essential
for
IL-12
production
TLRs
but,
surprisingly,
Irak2