Proteasome Inhibition Enhances Lysosome-mediated Targeted Protein Degradation
bioRxiv (Cold Spring Harbor Laboratory),
Journal Year:
2025,
Volume and Issue:
unknown
Published: Feb. 1, 2025
ABSTRACT
Proteasome
inhibitor
drugs
are
currently
used
in
the
clinic
to
treat
multiple
myeloma
and
mantle
cell
lymphoma.
These
inhibitors
cause
accumulation
of
undegraded
proteins,
thus
inducing
proteotoxic
stress
consequent
death.
However,
cancer
cells
counteract
this
effect
by
activating
an
adaptive
response
through
transcription
factor
Nuclear
erythroid
2-related
1
(NRF1,
also
known
as
NFE2L1).
NRF1
induces
transcriptional
upregulation
proteasome
autophagy/lysosomal
genes,
thereby
reducing
diminishing
effectiveness
inhibition.
While
suppressing
protective
autophagy
is
one
potential
strategy,
here
we
investigated
whether
heightened
could
instead
be
leveraged
therapeutically.
To
end,
designed
autophagy-targeting
chimera
(AUTAC)
compound
selectively
degrade
anti-apoptotic
protein
Mcl1
via
lysosome.
Our
results
show
that
lysosome-mediated
targeted
degradation
significantly
amplified
presence
inhibition,
a
NRF1-dependent
manner.
The
combination
carfilzomib
AUTAC
synergistically
promoted
death
both
wild-type
inhibitor-resistant
lung
cells.
Thus,
our
work
offers
novel
strategy
for
enhancing
efficacy
exploiting
response.
More
broadly,
study
establishes
framework
amplifying
degradation,
with
applications
therapeutics
beyond.
Language: Английский
Deletion of Nrf1α exacerbates oxidative stress-induced cellular senescence by disrupting cell homeostasis
Da Lyu,
No information about this author
Meng Wang,
No information about this author
Lu Qiu
No information about this author
et al.
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research,
Journal Year:
2025,
Volume and Issue:
unknown, P. 119970 - 119970
Published: April 1, 2025
Language: Английский
NFE2L1 as a central regulator of proteostasis in neurodegenerative diseases: interplay with autophagy, ferroptosis, and the proteasome
Frontiers in Molecular Neuroscience,
Journal Year:
2025,
Volume and Issue:
18
Published: May 1, 2025
Maintaining
proteostasis
is
critical
for
neuronal
health,
with
its
disruption
underpinning
the
progression
of
neurodegenerative
diseases
such
as
Alzheimer's,
Parkinson's,
and
Huntington's
diseases.
Nuclear
Factor
Erythroid
2-Related
1
(NFE2L1)
has
emerged
a
key
regulator
proteostasis,
integrating
proteasome
function,
autophagy,
ferroptosis
to
counteract
oxidative
stress
protein
misfolding.
This
review
synthesizes
current
knowledge
on
role
NFE2L1
in
maintaining
homeostasis,
focusing
mechanisms
mitigating
proteotoxic
supporting
cellular
offering
protection
against
neurodegeneration.
Furthermore,
we
discuss
pathological
implications
dysfunction
explore
potential
therapeutic
target.
By
highlighting
gaps
understanding
presenting
future
research
directions,
this
aims
elucidate
NFE2L1's
advancing
treatment
strategies
Language: Английский
Small-molecule activators of NRF1 transcriptional activity prevent protein aggregation
Jindr̂ich Sedláĉek,
No information about this author
Zuzana Smahelova,
No information about this author
Michael Adamek
No information about this author
et al.
Biomedicine & Pharmacotherapy,
Journal Year:
2025,
Volume and Issue:
183, P. 117864 - 117864
Published: Jan. 29, 2025
Language: Английский
Increased Oxidative Stress and Autophagy in NGLY1 Patient iPSC-derived Neural Stem Cells
Zeenat A. Shyr,
No information about this author
Soukaina Amniouel,
No information about this author
Kofi Owusu-Ansah
No information about this author
et al.
Experimental Cell Research,
Journal Year:
2025,
Volume and Issue:
unknown, P. 114540 - 114540
Published: April 1, 2025
NGLY1
(N-glycanase)
is
a
de-glycosylating
enzyme
that
promotes
clearance
of
misfolded
glycan
proteins.
deficiency
leads
to
disease
pathology
with
varied
symptoms,
including
severe
neurological
defects.
There
are
no
therapeutic
options
currently
available
for
the
treatment
this
rare
disease.
With
goal
finding
potential
avenues,
we
performed
comprehensive
characterization
aberrant
cellular
stress
pathways
in
patient
relevant
model
deficiency.
For
more
accurate
study
without
other
confounding
factors,
compared
differences
between
iPSC-derived
neural
stem
cells
carrying
commonly
occurring
nonsense
mutation
c.1201A>T
(p.R401X)
and
their
genetically
similar
CRISPR-corrected
isogenic
controls.
Our
findings
demonstrate
an
upregulation
ER
stress,
increased
autophagic
flux
significant
signs
oxidative
stress.
These
results
provide
new
insights
into
dysfunctions
associated
disorder.
Moreover,
they
point
better
establishing
reliable
high
throughput
phenotypic
assays
can
be
utilized
drug
discovery.
Language: Английский
Impact of proteostasis workload on sensitivity to proteasome inhibitors in multiple myeloma
Clinical and Experimental Medicine,
Journal Year:
2025,
Volume and Issue:
25(1)
Published: May 26, 2025
Language: Английский
Biologic activity and treatment resistance to gastrointestinal cancer: the role of circular RNA in autophagy regulation
Bo Zhang,
No information about this author
Zhe Li,
No information about this author
Guoliang Ye
No information about this author
et al.
Frontiers in Oncology,
Journal Year:
2024,
Volume and Issue:
14
Published: Aug. 30, 2024
Circular
RNAs
(circRNAs)
lack
the
5'-end
methylated
guanine
cap
structure
and
3'
polyadenylate
tail
structure,
classifying
it
as
a
non-coding
RNA.
With
extensive
investigation
of
circRNA,
its
role
in
regulating
cell
death
has
garnered
significant
attention
recent
years,
establishing
recognized
participant
cancer's
biological
processes.
Autophagy,
an
essential
pathway
programmed
(PCD),
involves
formation
autophagosomes
using
lysosomes
to
degrade
cellular
contents
under
regulation
various
autophagy-related
(ATG)
genes.
Numerous
studies
have
demonstrated
that
circRNA
can
modulate
activity
cancer
cells
by
influencing
autophagy
pathway,
exhibiting
dualistic
suppressing
or
promoting
carcinogenesis.
In
this
review,
we
comprehensively
analyze
how
impacts
progression
gastrointestinal
(GIC).
Additionally,
discuss
drug
resistance
phenomena
associated
with
GIC.
This
review
offers
valuable
insights
into
exploring
potential
targets
for
prognosis
treatment
strategies
related
Language: Английский
Deletion of Nrf1 exacerbates oxidative stress-induced cellular senescence by disrupting the cell homeostasis
Da Lyu,
No information about this author
Meng Wang,
No information about this author
Lu Qiu
No information about this author
et al.
bioRxiv (Cold Spring Harbor Laboratory),
Journal Year:
2024,
Volume and Issue:
unknown
Published: March 9, 2024
Abstract
Cellular
senescence
has
been
accepted
as
a
fundamental
contributor
to
ageing
and
variety
of
age-related
diseases,
in
which
oxidative
stress
further
recognized
play
critical
initiation
role.
However,
the
anti-senescence
potential
antioxidant
nuclear
factor
erythroid-derived
2-like
1
(Nrf1,
encoded
by
Nfe2l1
)
remains
elusive
date,
even
though
hitherto
accumulating
evidence
demonstrates
that
it
is
an
indispensable
redox-determining
transcription
for
maintaining
cellular
homeostasis
organ
integrity.
Herein,
we
discovered
deletion
Nrf1
resulted
markedly
elevated
characteristics
Nrf1α
−/−
cells,
characterized
two
distinct
experimental
models
induced
stress,
are
evinced
typically
heightened
activity
senescence-associated
β-galactosidase
progressive
secretory
phenotype
(SASP),
along
with
decreased
cell
vitality
intensified
cycle
arrest.
Further
investigation
also
uncovered
such
acceleration
stress-induced
from
disturbance
homeostasis,
because
deficiency
leads
STAG2-
SMC3-dependent
chromosomal
stability
disruption
autophagy
dysfunction,
accompanied
excessive
accumulation
Nrf2
(encoded
Nfe2l2
).
The
aberrant
hyperactive
cannot
effectively
counteract
escalating
caused
.
Overall,
this
study
provided
series
supporting
indeed
exerts
essential
protective
function
against
senescence,
thereby,
highlighting
its
primary
contribution
robust
homeostasis.
Language: Английский
Activation of the 26S Proteasome to Reduce Proteotoxic Stress and Improve the Efficacy of PROTACs
ACS Pharmacology & Translational Science,
Journal Year:
2024,
Volume and Issue:
8(1), P. 21 - 35
Published: Dec. 16, 2024
The
26S
proteasome
degrades
the
majority
of
cellular
proteins
and
affects
all
aspects
life.
Therefore,
abundance,
proper
assembly,
activity
in
different
life
contexts
need
to
be
precisely
controlled.
Impaired
is
considered
a
causative
factor
several
serious
disorders.
Recent
advances
biology
have
revealed
that
can
activated
by
factors
or
small
molecules.
Thus,
ubiquitin-dependent
degradation
has
effects
such
as
extending
lifespan
models,
preventing
accumulation
protein
aggregates,
reducing
their
negative
impact
on
cells.
Increased
proteasome-mediated
reduces
proteotoxic
stress
potentially
improve
efficacy
engineered
degraders,
PROTACs,
particularly
situations
characterized
malfunction.
Here,
emerging
ideas
recent
insights
into
pharmacological
activation
at
transcriptional
posttranslational
levels
are
summarized.
Language: Английский