Nature Communications,
Journal Year:
2024,
Volume and Issue:
15(1)
Published: March 19, 2024
Abstract
ADP-ribosylation
is
a
reversible
post-translational
modification
involved
in
various
cellular
activities.
Removal
of
requires
(ADP-ribosyl)hydrolases,
with
macrodomain
enzymes
being
major
family
this
category.
The
pathogen
Legionella
pneumophila
mediates
atypical
ubiquitination
host
targets
using
the
SidE
effector
process
that
involves
ubiquitin
on
arginine
42
as
an
obligatory
step.
Here,
we
show
MavL
regulates
pathway
by
reversing
ADP-ribosylation,
likely
to
minimize
potential
detrimental
effects
caused
modified
ubiquitin.
We
determine
crystal
structure
ADP-ribose-bound
MavL,
providing
structural
insights
into
recognition
ADP-ribosyl
group
and
catalytic
mechanism
its
removal.
Further
analyses
reveal
DUF4804
class
MavL-like
whose
representative
members
unique
selectivity
for
mono-ADP-ribosylated
residue
synthetic
substrates.
find
such
are
also
present
eukaryotes,
exemplified
two
previously
uncharacterized
(ADP-ribosyl)hydrolases
Drosophila
melanogaster
.
Crystal
structures
several
proteins
provide
specificity
shared
mode
ADP-ribose
interaction
distinct
from
characterized
macrodomains.
Collectively,
our
study
reveals
new
regulatory
layer
SidE-catalyzed
expands
current
understanding
enzymes.
The Journal of Cell Biology,
Journal Year:
2019,
Volume and Issue:
218(6), P. 1776 - 1786
Published: April 18, 2019
Ubiquitination
regulates
many
essential
cellular
processes
in
eukaryotes.
This
post-translational
modification
(PTM)
is
typically
achieved
by
E1,
E2,
and
E3
enzymes
that
sequentially
catalyze
activation,
conjugation,
ligation
reactions,
respectively,
leading
to
covalent
attachment
of
ubiquitin,
usually
lysine
residues
substrate
proteins.
Ubiquitin
can
also
be
successively
linked
one
the
seven
on
ubiquitin
form
distinctive
forms
polyubiquitin
chains,
which,
depending
upon
used
length
dictate
fate
Recent
discoveries
revealed
this
code
further
expanded
PTMs
such
as
phosphorylation,
acetylation,
deamidation,
ADP-ribosylation,
components
ubiquitination
machinery,
or
both.
These
provide
additional
regulatory
nodes
integrate
development
insulting
signals
with
homeostasis.
Understanding
precise
roles
these
regulation
signaling
will
new
insights
into
mechanisms
treatment
various
human
diseases
ubiquitination,
including
neurodegenerative
diseases,
cancer,
infection,
immune
disorders.
Science,
Journal Year:
2019,
Volume and Issue:
364(6442), P. 787 - 792
Published: May 23, 2019
Divergent
protein
kinase
SidJ
is
a
produced
by
Legionella
pneumophila
that
orchestrates
this
intracellular
pathogen's
establishment
within
the
host
cell.
prevents
lysosome
fusion
with
vacuole,
which
bacterium
resides
and
replicates.
also
modulates
toxicity
of
SidE
family
ubiquitin
ligases
catalyze
phosphoribosyl-linked
ubiquitination.
Black
et
al.
discovered
activated
calmodulin.
Furthermore,
although
has
pseudokinase
fold,
it
does
not
phosphorylate
proteins
but
polyglutamylates
them
instead.
The
in
vivo
relevance
mechanism
for
bacterial
infectivity
was
verified
natural
reservoir
Acanthamoeba
castellanii
.
Science
,
issue
p.
787
Molecular Cell,
Journal Year:
2019,
Volume and Issue:
77(1), P. 164 - 179.e6
Published: Nov. 12, 2019
The
family
of
bacterial
SidE
enzymes
catalyzes
non-canonical
phosphoribosyl-linked
(PR)
serine
ubiquitination
and
promotes
infectivity
Legionella
pneumophila.
Here,
we
describe
identification
two
effectors
that
reverse
PR
are
thus
named
deubiquitinases
for
(DUPs;
DupA
DupB).
Structural
analyses
revealed
ubiquitin
ligases
harbor
a
highly
homologous
catalytic
phosphodiesterase
(PDE)
domain.
However,
unlike
ligases,
displays
increased
affinity
to
PR-ubiquitinated
substrates,
which
allows
cleave
from
substrates.
Interfering
with
DupA-ubiquitin
binding
switches
its
activity
toward
SidE-type
ligase.
Given
the
high
exploited
catalytically
inactive
mutant
trap
identify
more
than
180
host
proteins
in
Legionella-infected
cells.
Proteins
involved
endoplasmic
reticulum
(ER)
fragmentation
membrane
recruitment
Legionella-containing
vacuoles
(LCV)
emerged
as
major
targets.
global
map
substrates
provides
critical
insights
into
host-pathogen
interactions
during
infection.
Proceedings of the National Academy of Sciences,
Journal Year:
2019,
Volume and Issue:
116(47), P. 23518 - 23526
Published: Nov. 5, 2019
Posttranslational
protein
modification
by
ubiquitin
(Ub)
is
a
central
eukaryotic
mechanism
that
regulates
plethora
of
physiological
processes.
Recent
studies
unveiled
an
unconventional
type
ubiquitination
mediated
the
SidE
family
Legionella
pneumophila
effectors,
such
as
SdeA,
catalyzes
conjugation
Ub
to
serine
residue
target
proteins
via
phosphoribosyl
linker
(hence
named
PR-ubiquitination).
Comparable
deubiquitinases
in
canonical
pathway,
here
we
show
2
paralogous
Lpg2154
(DupA;
deubiquitinase
for
PR-ubiquitination)
and
Lpg2509
(DupB),
reverse
PR-ubiquitination
specific
removal
phosphoribosyl-Ub
from
substrates.
Both
DupA
DupB
are
fully
capable
rescuing
Golgi
fragmentation
phenotype
caused
exogenous
expression
SdeA
mammalian
cells.
We
further
deletion
these
genes
results
significant
accumulation
PR-ubiquitinated
species
host
cells
infected
with
In
addition,
have
identified
list
targets
play
role
modulating
association
Legionella-containing
vacuoles.
Together,
our
data
establish
complete
deubiquitination
cycle
demonstrate
intricate
control
has
over
this
unusual
Ub-dependent
posttranslational
modification.
