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Unique N-linked glycosylation of CasBrE Env influences its stability, processing, and viral infectivity but not its neurotoxicity.
[canavan disease]
The
envelope
protein
(
Env
)
from
the
CasBrE
murine
leukemia
virus
(
MLV
)
can
cause
acute
spongiform
neurodegeneration
analogous
to
that
induced
by
prions
.
Upon
central
nervous
system
(
CNS
)
infection
,
Env
is
expressed
as
multiple
isoforms
owing
to
differential
asparagine
(
N
)
-
linked
glycosylation
.
Because
N-
glycosylation
can
affect
protein
folding
,
stability
,
and
quality
control
,
we
explored
whether
unique
CasBrE
Env
glycosylation
features
could
influence
neurovirulence
.
CasBrE
Env
possesses
6
/
8
consensus
MLV
glycosylation
sites
(
gs
)
but
is
missing
gs
3
and
gs
5
and
contains
a
putative
site
(
gs
*
)
.
Twenty
-
nine
mutants
were
generated
by
modifying
these
three
sites
,
individually
or
in
combination
,
to
mimic
the
amino
acid
sequence
in
the
nonneurovirulent
Friend
57
MLV
.
Three
basic
viral
phenotypes
were
observed
:
replication
defective
(
dead
;
titer
<
1
focus-forming
unit
[
FFU
]
/
ml
)
,
replication
compromised
(
RC
)
(
titer
=
10
(
2
)
to
10
(
5
)
FFU
/
ml
)
;
and
wild-
type
-like
(
WTL
)
(
titer
>
10
(
5
)
FFU
/
ml
)
.
Env
protein
was
undetectable
in
dead
mutants
,
while
RC
and
WTL
mutants
showed
variations
in
Env
expression
,
processing
,
virus
incorporation
,
virus
entry
,
and
virus
spread
.
The
newly
introduced
gs
3
and
gs
5
sites
were
glycosylated
,
whereas
gs
*
was
not
.
Six
WTL
mutants
tested
in
mice
showed
no
clear
attenuation
in
disease
onset
or
severity
versus
controls
.
Furthermore
,
three
RC
viruses
tested
by
neural
stem
cell
(
NSC
)
-
mediated
brainstem
dissemination
also
induced
acute
spongiosis
.
Thus
,
while
unique
N-
glycosylation
affected
structural
features
of
Env
involved
in
protein
stability
,
proteolytic
processing
,
and
virus
assembly
and
entry
,
these
changes
had
minimal
impact
on
CasBrE
Env
neurotoxicity
.
These
findings
suggest
that
the
Env
protein
domains
responsible
for
spongiogenesis
represent
highly
stable
elements
upon
which
the
more
variable
viral
functional
domains
have
evolved
.
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