UFMylation
involves
the
covalent
modification
of
substrate
proteins
with
UFM1
(Ubiquitin-fold
modifier
1)
and
is
important
for
maintaining
ER
homeostasis.
Stalled
translation
triggers
ER-bound
ribosomes
activates
C53-mediated
autophagy
to
clear
toxic
polypeptides.
C53
contains
noncanonical
shuffled
ATG8-interacting
motifs
(sAIMs)
that
are
essential
ATG8
interaction
initiation.
However,
mechanistic
basis
sAIM-mediated
remains
unknown.
Here,
we
show
sAIMs
conserved
across
eukaryotes
but
secondarily
lost
in
fungi
various
algal
lineages.
Biochemical
assays
showed
unicellular
alga
Chlamydomonas
reinhardtii
has
a
functional
pathway,
refuting
assumption
linked
multicellularity.
Comparative
structural
analyses
revealed
both
bind
C53,
distinct
way.
Conversion
into
canonical
AIMs
impaired
binding
UFM1,
while
strengthening
binding.
Increased
led
autoactivation
pathway
sensitization
Arabidopsis
thaliana
stress.
Altogether,
our
findings
reveal
an
ancestral
role
UFMylation-dependent
fine-tuning
activation.
Eukaryotes
have
evolved
various
quality
control
mechanisms
to
promote
proteostasis
in
the
endoplasmic
reticulum
(ER).
Selective
removal
of
certain
ER
domains
via
autophagy
(termed
as
ER-phagy)
has
emerged
a
major
mechanism.
However,
degree
which
ER-phagy
is
employed
by
other
branches
ER-quality
remains
largely
elusive.
Here,
we
identify
cytosolic
protein,
C53,
that
specifically
recruited
autophagosomes
during
ER-stress,
both
plant
and
mammalian
cells.
C53
interacts
with
ATG8
distinct
binding
epitope,
featuring
shuffled
interacting
motif
(sAIM).
senses
proteotoxic
stress
lumen
forming
tripartite
receptor
complex
ER-associated
ufmylation
ligase
UFL1
its
membrane
adaptor
DDRGK1.
The
C53/UFL1/DDRGK1
activated
stalled
ribosomes
induces
degradation
internal
or
passenger
proteins
ER.
Consistently,
mutants
are
highly
susceptible
stress.
Thus,
forms
an
ancient
pathway
bridges
selective
ribosome-associated
British Journal of Pharmacology,
Год журнала:
2020,
Номер
177(8), С. 1709 - 1718
Опубликована: Фев. 5, 2020
Proteolysis‐targeting
chimeras
are
a
new
drug
modality
that
exploits
the
endogenous
ubiquitin
proteasome
system
to
degrade
protein
of
interest
for
therapeutic
benefit.
As
first‐generation
proteolysis‐targeting
have
now
entered
clinical
trials
oncology
indications,
it
is
timely
consider
theoretical
safety
risks
inherent
with
this
which
include
off‐target
degradation,
intracellular
accumulation
natural
substrates
E3
ligases
used
in
system,
saturation
by
ubiquitinated
proteins,
and
liabilities
associated
“hook
effect”
This
review
describes
vitro
non‐clinical
vivo
data
provide
mechanistic
insight
these
approaches
being
mitigate
next
generation
chimera
molecules
extend
applications
beyond
life‐threatening
diseases.
Physiological Reviews,
Год журнала:
2022,
Номер
102(3), С. 1393 - 1448
Опубликована: Фев. 21, 2022
ER-phagy
(reticulophagy)
defines
the
degradation
of
portions
endoplasmic
reticulum
(ER)
within
lysosomes
or
vacuoles.
It
is
part
self-digestion
(i.e.,
autophagic)
programs
recycling
cytoplasmic
material
and
organelles,
which
rapidly
mobilize
metabolites
in
cells
confronted
with
nutrient
shortage.
Moreover,
selective
clearance
ER
subdomains
participates
control
size
activity
during
stress,
reestablishment
homeostasis
after
stress
resolution,
removal
parts
aberrant
potentially
cytotoxic
has
been
segregated.
relies
on
individual
and/or
concerted
activation
receptors,
peripheral
integral
membrane
proteins
that
share
presence
LC3/Atg8-binding
motifs
their
cytosolic
domains.
involves
physical
separation
from
bulk
network
delivery
to
endolysosomal/vacuolar
catabolic
district.
This
last
step
accomplished
by
a
variety
mechanisms
including
macro-ER-phagy
(in
fragments
are
sequestered
double-membrane
autophagosomes
eventually
fuse
lysosomes/vacuoles),
micro-ER-phagy
directly
engulfed
endosomes/lysosomes/vacuoles),
direct
fusion
ER-derived
vesicles
lysosomes/vacuoles.
dysfunctional
specific
human
diseases,
its
regulators
subverted
pathogens,
highlighting
crucial
role
for
cell
organism
life.
Protein
concentrations
are
set
by
a
complex
interplay
between
gene-specific
regulatory
processes
and
systemic
factors,
including
cell
volume
shared
gene
expression
machineries.
Elucidating
this
is
crucial
for
discerning
designing
systems.
We
quantitatively
characterized
factors
that
affect
transcription
translation
genome-wide
Escherichia
coli
across
many
conditions.
The
results
revealed
two
design
principles
make
regulation
of
insulated
from
machineries:
RNA
polymerase
activity
fine-tuned
to
match
translational
output,
characteristics
similar
most
messenger
RNAs
(mRNAs).
Consequently,
in
bacteria,
protein
concentration
primarily
at
the
promoter
level.
A
simple
mathematical
formula
relates
activities
growth
conditions,
enabling
quantitative
inference
omics
data.
