Angewandte Chemie International Edition,
Год журнала:
2022,
Номер
62(12)
Опубликована: Дек. 31, 2022
Abstract
Lysine
acetylation
is
a
charge‐neutralizing
post‐translational
modification
of
proteins
bound
by
bromodomains
(Brds).
A
1,2,4‐triazole
amino
acid
(ApmTri)
was
established
as
acetyllysine
(Kac)
mimic
recruiting
Brds
the
BET
family
in
contrast
to
glutamine
commonly
used
for
simulating
this
modification.
Optimization
triazole
substituents
and
side
chain
spacing
allowed
Brd
recruitment
ApmTri‐containing
peptides
with
affinities
similar
native
substrates.
Crystal
structures
complex
two
revealed
binding
mode
which
mirrored
that
Kac
ligands.
ApmTri
genetically
encoded
recombinant
co‐enriched
BRD3(2)
from
cellular
lysates.
This
interaction
blocked
inhibitor
JQ1.
With
ApmTri,
biochemistry
now
provided
stable
reflecting
charge
neutralization
recruitment,
allowing
new
investigations
into
vitro
vivo.
Cellular and Molecular Life Sciences,
Год журнала:
2024,
Номер
81(1)
Опубликована: Июль 9, 2024
Nod-like
receptor
family
pyrin-containing
protein
3
(NLRP3)
inflammasome
plays
a
pathologic
role
in
metabolic
dysfunction-associated
steatohepatitis
(MASH),
but
the
molecular
mechanism
regulating
NLRP3
activation
hepatocellular
lipotoxicity
remains
largely
unknown.
Bromodomain-containing
4
(BRD4)
has
emerged
as
key
epigenetic
reader
of
acetylated
lysine
residues
enhancer
regions
that
control
transcription
genes.
The
aim
this
study
is
to
investigate
if
and
how
BRD4
regulated
pyroptosis
MASH.
Using
AML12
primary
mouse
hepatocytes
stimulated
by
palmitic
acid
(PA)
an
vitro
model
lipotoxicity,
we
found
targeting
genetic
knockdown
or
selective
inhibitor
MS417
protected
against
hepatosteatosis;
protective
effect
was
attributed
inhibiting
reducing
expression
Caspase-1,
gasdermin
D
(GSDMD),
interleukin
(IL)-1β
IL-6.
Moreover,
inhibition
limited
voltage-dependent
anion
channel-1
(VDAC1)
oligomerization
PA-treated
hepatocytes,
thereby
suppressing
activation.
Additionally,
enhanced
MASH
livers
humans.
Mechanistically,
upregulated
during
turn
modulated
active
mark
H3K27ac
at
promoter
Vdac
Gsdmd
genes,
enhancing
VDAC
GSDMD.
Altogether,
our
data
provide
novel
insights
into
mechanisms
underlying
activating
promoting
GSDMD-mediated
lipotoxicity.
Thus,
might
serve
therapeutic
target
for
treatment
Biomedicines,
Год журнала:
2024,
Номер
12(9), С. 2001 - 2001
Опубликована: Сен. 3, 2024
Gastric
cancer
(GC)
remains
a
significant
public
health
concern
because
of
its
lethality,
underscoring
the
need
for
deeper
insights
into
molecular
mechanisms.
Recent
studies
have
increasingly
highlighted
role
epigenetic
modifications
as
critical
players
in
progression.
Despite
their
importance,
research
specifically
addressing
factors
GC
is
relatively
scarce.
This
paper
seeks
to
bridge
that
gap
by
examining
recent
literature
elucidates
landscape
associated
with
GC.
The
investigation
long
noncoding
RNAs
(lncRNAs)
has
revealed
substantial
involvement
gene
dysregulation
and
alterations
within
tumors.
Notably,
lncRNAs
such
LINC00853
LINC01266
been
identified
contributors
modulation
expression.
Furthermore,
overexpression
Angewandte Chemie International Edition,
Год журнала:
2022,
Номер
62(12)
Опубликована: Дек. 31, 2022
Abstract
Lysine
acetylation
is
a
charge‐neutralizing
post‐translational
modification
of
proteins
bound
by
bromodomains
(Brds).
A
1,2,4‐triazole
amino
acid
(ApmTri)
was
established
as
acetyllysine
(Kac)
mimic
recruiting
Brds
the
BET
family
in
contrast
to
glutamine
commonly
used
for
simulating
this
modification.
Optimization
triazole
substituents
and
side
chain
spacing
allowed
Brd
recruitment
ApmTri‐containing
peptides
with
affinities
similar
native
substrates.
Crystal
structures
complex
two
revealed
binding
mode
which
mirrored
that
Kac
ligands.
ApmTri
genetically
encoded
recombinant
co‐enriched
BRD3(2)
from
cellular
lysates.
This
interaction
blocked
inhibitor
JQ1.
With
ApmTri,
biochemistry
now
provided
stable
reflecting
charge
neutralization
recruitment,
allowing
new
investigations
into
vitro
vivo.
