Download Permeability properties of lysosomal membranes

Bioscience Reports 3, 207-216 (1983)
Printed in Great Britain
207
P e r m e a b i l i t y p r o p e r t i e s of l y s o s o m a l m e m b r a n e s
Review
Kevin DOCHERTY, Gerald A. MAGUIRE~ and C. Nicholas HALES
Department of Clinical Biochemistry, University of Cambridge,
Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QR, U.K.
L y s o s o m e s are involved in the cellular degradation of material
either initially present in the cell or brought into the cell by phagocytosis or endocytosis. This degradative process, which occurs in an
acidic environment, produces metabolites such as peptides and amino
acids~ n u c l e o s i d e s , and sugars which may subsequently accumulate
within the lysosome.
It is therefore important for osmotic reasons,
and for optimal utilization of these metabolites, to have a system
whereby the degradative products can pass through the lysosomal
membrane.
This can be achieved either by passive diffusion or via a
specific transport mechanism. Furthermore, maintenance of the acidic
m i l i e u n e c e s s a r y for o p t i m a l a c t i v i t y of the ]ysosomal enzymes
requires concentration of hydrogen ions within the lysosome.
This
hydrogen-ion gradient may be maintained either by a Gibbs-Donnan
equilibrium or via an ATP-dependent proton pump in the lysosomal
membrane.
It is these permeability and hydrogen-ion-concentrating
properties of the lysosomal membrane which will be discussed in this
review.
Our interest in the mechanism by which the products of lysosomal
digestion cross the lysosomal membrane to reach the cytosol arose
from a hypothesis concerning the evolutionary origins of polypeptide
hormones.
Most polypeptide hormones are synthesized as propolypeptides which are cleaved at sites usually marked by pairs of basic
amino acids (Docherty & Steiner, 1992).
In considering the problem
posed by the existence of prohormones~ it was suggested that they
c o u l d be explained if the evolutionary origin of polypeptide hormones
was from a more p r i m i t i v e process of lysosomal proteolysis in
u n i c e l l u l a r o r g a n i s m s (Hales~ 1978~ Hales & D o c h e r t y , 1979).
Polypeptide fragments produced by this means within the lumen of the
secondary lysosome would potentially be capable of interaction with
m e m b r a n e components in the structure of the secondary lysosomal
membrane.
Such membrane proteins could include plasma-membrane
transporters.
One of the most important processes regulated by
p o l y p e p t i d e h o r m o n e s is m e m b r a n e t r a n s p o r t .
It was therefore
suggested that the membrane of the secondary lysosome would contain
transport mechanisms.
Studies on the permeability properties of the lysosomal membrane
to metabolites such as sugars and amino acids had up to that time
been interpreted as indicative of simple diffusion (Reijngoud & Tager,
1977).
We therefore undertook a reinvestigation of the problem as it
related to sugar permeability. In this review we describe the methods
available for the study of metabolite permeability of lysosomes and
01983
The Biochemical Society
208
DOCHERTY ET AL.
the results obtained for sugars, peptides, and amino acids, and how
these latter results pertain to the genetic disorder cystinosis. We will
then b r i e f l y review experiments on the hydrogen-ion-concentrating
properites of the lysosomal membrane.
The Permeability of Lysosomes to Sugars
One of the most r e a d i l y applicable methods for studying the
p e r m e a b i l i t y of Iysosomes to sugars and other metabolites is the
o s m o t i c - p r o t e c t i o n method, which is based on the experiments of
Berthet et al. (1951). When placed in media of low osmotic pressure,
rat liver lysosomes rupture, as shown by the release of their specific
enzyme content.
On the other hand, lysosomes placed in isotonic
solutions of impermeable substances such as sucrose remain intact in
solution for hours.
Between these two extremes, a time-dependent
rupture of lysosomes occurs in isotonic solutions of substances such as
glucose.
These substances are believed to enter the lysosome as a
result of the concentration gradient established in isotonic solutions.
Water is then drawn into the organelle with resultant swelling and
eventual rupture.
The extent to which different substances protect
lysosomes against such osmotic rupture is a measure of the impermeability of the lysosomal membrane towards them.
The use of o s m o t i c swelling to m e a s u r e permeability has a
precedent in the early investigation of red-cell permeability.
The
'haemolysis-point' method (3acobs, 193at) involved suspending red ceils
in i s o t o n i c solutions of various compounds.
Permeant compounds
caused osmotic lysis of the cells, and the time taken to reach a
degree of haemolysis (measured by a decrease in turbidity) was an
indirect measure of the rate of entry of the compound. Much of our
e a r l y u n d e r s t a n d i n g of red-cell sugar transport was based on the
results obtained using an osmotic-swelling method (LeFevre, 1961), and
this method has also been used to investigate the sugar permeability
of chromaffin granules (Perlman, 1976), and Golgi apparatus vesicles
(White et al., 1980).
The most extensive early studies of lysosomal sugar permeability
using osmotic protection were those of Lloyd (1969). He observed, in
agreement with the vacuolation experiments (see below) of Cohn and
Ehrenreich (1969), that various disaccharides did not cause lysosomal
breakage.
He also compared the behaviour of a wide range of
monosaccharides and hexitols. Quite marked differences were observed
between the relative permeabilities of these substances. The hexitols
sorbito], mannitol, and inositol provided good osmotic protection.
At
t h e e x t r e m e s of the monosaccharides causing osmotic lysis were
e r y t h r i t o l ( v e r y f a s t ) and D - g l u c o s e ( v e r y s l o w ) .
The large
differences which were observed between the sugars and hexitols were
a t t r i b u t e d to d i f f e r e n c e s in t h e i r r a t e s of diffusion across the
lysosomal membrane.
Docherty et al. (1979) decided to reinvestigate this problem with
the aim of determining to what extent, within the limitations of the
technique, known criteria of a sugar-transport process could be applied
to the system.
Where comparable studies were carried out their
results agreed closely with those of Lloyd (1969).
They concluded
that their more extensive investigations were most readily explained by
PERMEABILITY PROPERTIES OF LYSOSOMAL MEMBRANES
209
the presence of one or more transport processes as evidenced by the
f o l l o w i n g c r i t e r i a : sugar specificity; sterospecificity~ inhibition by
cytochalasin B and phlorrhizin~ competitionl and a QI0 for uptake of
approximately 2.8.
It was proposed that sugar uptake took place by
facilitated diffusion. Docherty et al. (1979) also discussed the f a c t
t h a t the ranking of the r e l a t i v e rates of net uptake would not
n e c e s s a r i l y r e f l e c t the order of permeability at physiological (as
opposed to 0.25 M) concentrations. The high concentration of sugars
dictated by the osmotic protection method makes it likely that the
uptake of sugars is occurring at a concentration considerably in excess
.of their affinity constant for the transport process.
Under these
.conditions the rate of net uptake, which is the difference between
influx and efflux, can become quite slow. The reason for this is that
influx proceeds at an almost maximal velocity whilst, due to rapid
increase of the lysosomal sugar concentration~ the rate of efflux also
becomes very rapid with the diflerence between the two being quite
small.
This has been demonstrated mathematically by Stein (1967).
]For a series of compounds of decreasing affinity, at high concentrations the rate of net uptake may be in the inverse order of their
r e l a t i v e affinities for the uptake process.
Clearly the order will
reverse at some point since substances with an extremely low affinity
:[or the uptake process will not enter the lysosome at a measurable
rate.
S o m e w h a t surprisingly, in view of the different cell types
i[nvoJved, the order of net uptake established for rat liver lysosomes by
the osmotic protection method is the reverse of the affinities of these
sugars for the t r a n s p o r t m e c h a n i s m in the human e r y t h r o c y t e
(Docherty et al.~ 1979).
A prediction of this explanation of the
reversed order is that some sugars with a slow rate of net uptake
should have a higher affinity for the carrier than those with a high
rate of uptake.
They should therefore also inhibit the .uptake of
sugars with a high rate of net accumulation.
This prediction was
indeed verified experimentally (Docherty et al.~ 1979).
The affinity of glucose for the plasma-membrane transport system
varies from tissue to tissue.
The affinity constants for rat musc]%
a d i p o s e tissu% and liver are 8 mM (Post et al., 1971)7 7 mM
(Whitesell & Gliemann, 1979), and 66 mM (Elliott & Craik, 1982)
respectively. If the sugar-transport system in lysosomes is similar or
identical to that of the plasma membrane then the above kinetic
c o n s i d e r a t i o n s i n d i c a t e t h a t the rate of net glucose uptake into
lysosomes of muscle and adipose tissue should be considerably slower
t h a n t h a t into liver lysosomes.
This has been found to be true
e x p e r i m e n t a l l y using the osmotic protection method (Docherty &
Hales, 1980; K D o c h e r t y , GA Maguire & CN Hales, manuscript
submitted).
The p e r m e a b i l i t y of lysosomes to sugars can also be measured
directly using radioactively labelled sugars.
In order to study the
uptake of radioactively labelled sugars it is necessary to use a highly
purified preparation of lysosomes. One approach used to obtain such a
preparation is to alter the buoyant density of the lysosomes by prior
a c c u m u l a t i o n of low-density material.
If rats are injected intraperitoneally with Triton WR-1339 the detergent is accumulated in the
lysosomes
( L e i g h t o n et al., 1968).
The m o d i f i e d l y s o s o m e s
( ' t r i t o s o m e s ' ) may be highly p u r i f i e d Irom a liver homogenate
prepared # days after the injection (Trouet, 197#).
Maguire et al.
210
DOCHERTY ET AL.
( i 9 8 3 ) investigated the entry of D-[~H]glucose into tritosomes by a
method which involved separating them from the incubation medium by
centrifugation through silicone oil.
The internal water space (2.2 -+
0.2 pl/mg of protein, mean -+ SEM, n = 12) of the pelleted tritosomes
was 6396 of the total water space of the pellet. The rate of entry of
D - E 3 H ] g l u c o s e at high concentrations was, however, too great for
accurate estimation of linear rates of influx. Using concentrations at
which it was possible to measure linear rates of influx (up to 20
m M ) , the r a t e of entry of D-[~H]glucose exhibited concentration
dependence indicative of saturation with a K m of 48 -+ Ig mM (mean
+ SEM, n = t~).
As discussed above for a system that operated by
facilitated diffusion, the relative rates at which sugars enter lysosomes
at high concentrations may be in the reverse order of their affinities,
whereas at low concentrations the relative rates will be in the order
of their affinities.
At high concnetration (125 mM) D-El~C]ribose
entered purified lysosomes more quickly than D-El~C]glucose. At low
concentrations ( l raM), this order was reversed, thus confirming the
presence of a transport system (Maguire et aJ., 1983).
If a single
transport system was responsible for the entry of the sugars investigated then mutual competition between the sugars would be expected.
The uptake of D-Ei~C]glucose and D - [ I ~ C ] ribose was measured in the
presence of several competing sugars.
The order of competition in
both cases (2 deoxy-D-glucose < D-glucose < D-mannose < D-ribose)
was similar to that deduced from the direct uptake study and the
osmotic protection study.
Thus, it is likely that the sugars share a
transport system.
The Permeability of Lysosomes to Peptides and Amino Acids
The permeability of lysosomes to peptides and amino acids has
been studied by measuring vacuolation in intact cells, by the osmoticprotection method, and by the efflux of radioactively labelled amino
acids from preloaded lysosomes. The basis of the vacuolation method
is that during endocytosis, solubie molecules are taken up passively and
n o n - s p e c i f i c a l l y into endocytotic vesicles which fuse with primary
l y s o s o m e s to form secondary lysosomes.
Substances which cannot
p e r m e a t e the l y s o s o m a l m e m b r a n e a c c u m u l a t e in the secondary
lysosome, and the increased osmolarity of the interior results in water
influx and vacuolation. The process of vacuolation can be observed in
intact cells by phase-contrast microscopy. Electron-microscopic studies
in which acid phosphatase has been localized in the vacuoles have
confirmed that they are indeed secondary lysosomes. Vacuolation was
used by Cohn and E h r e n r e i c h (1969) to d e m o n s t r a t e that the
m e m b r a n e of the secondary lysosome of rabbit polymorphonuclear
leucocytes
was permeable
to m o n o s a c c h a r i d e s ,
and t h a t
oligosaccharides had to be degraded before their constitutent sugars
could e s c a p e from the s e c o n d a r y lysosome.
The e f f e c t on the
lysosome of incubating mouse peritoneal macrophages with peptides
was also s t u d i e d by Ehrenreich and Cohn (1969).
L-amino-acidcontaining peptides did not cause vacuolation, presumably because of
hydrolysis to permeable amino acids. However, from experiments using
a series of di- and t r i - p e p t i d e s containing D-amino acids, they
PERMEABILITY P R O P E R T I E S
OF LYSOSOMAL MEMBRANES
211
concluded that the Iysosomal membrane was impermeable to peptides
of mol.wt, greater than 230.
The osmotic-protection method was used by Lloyd (1971) to study
the permeability of lysosomes to peptides and amino acids. Because
this method necessitated the use of isotonic (0.25 M) solutions, and
few amino acids and peptides are sufficiently soluble, the study was
somewhat limited.
The results, however, were consistent with the
observations of Ehrenreich and Cohn (1969), but, as with the vacuolation method, the limitations of the system meant that experiments
which could differentiate between transport and non-transport mechanisms could not be attempted.
Overall, these two approaches led to
the conclusion that the ]ysosomal membrane was permeable to amino
acids and peptides with a rough mol.wt.-cut-off l i m i t of about 230.
A r e l a t e d t e c h n i q u e was used to s t u d y the permeability of
lysosomes to amino acid and peptide methyl esters at low concentrations ( l - 2 raM) (Goldman & KapJan, 1973).
L-amino acid methyl
esters caused a gradual loss of ]ysosoma] latency while the D-isomers
did not.
The explanation for this was that the m e t h y l esters were
more permeable than the free amino acids, and the L-amino acid
methyl esters were more readily hydrolysed by lysosomal esterases to
y i e l d the free L-amino acids, which would accumulate (and cause
Jysis) faster than the permeable methyl esters. Reeves (1979) used
this method to introduce radioactively labelled amino acids into rat
liver Jysosomes. When lysosomes were incubated in L - [ 3 H ] a m i n o acid
methyl esters at low concentrations (0.01 raM), they accumulated the
respective L-E3H]amino acid but did not rupture.
The efflux of the
L - E 3 H ] a m i n o acid was then s t u d i e d with a view to determining
whether it exhibited any of the characteristics of a transport-mediated
process, i.e. s a t u r a t i o n and counter- transport.
Lysosomes were
incubated in 30 mM L-leucine, for I0 rain at 37~ in order to preload
them w i t h L - l e u c i n e , and then the p r e p a r a t i o n was exposed to
L - [ 3 H ] l e u c i n e methyl ester [or 10 rain at 22~ to allow accumulation
of L-3H]leucine.
The lysosomes were then diluted 70-fold and the
efflux of L - [ 3 H ] l e u c i n e measured. The efflux of L-E3H]leucine from
the preloaded lysosomes was the same as that from control lysosomes,
s u g g e s t i n g t h a t if there was a transport system, then it did not
saturate at 30 raM.
Since hepatocyte amino-acid-transport systems
have K m values of about 5 mM (3oseph et al., 197g) the results
favoured a passive-diffusion model However, the interpretation of the
data as being indicative of the absence of a transport system may be
criticized.
It was assumed that a ]0-rain incubation with 30 mM
L-leucine would result in equilibration, since preliminary experiments
on the efflux of L--[3H]leucine showed that 9096 of the radioactive
amino acid had l e f t the lysosome in 10 min. If, however, there is a
transport system in ]ysosomes, the rate of equilibration of 30 mM
L-leucine would be much slower (Stein, 1967; see above). Hence, the
i n t e r n a l c o n c e n t r a t i o n of L - l e u c i n e a f t e r a I 0 - m i n incubation in 30 mM
L - l e u c i n e m a y not h a v e been close to 30 mM, and the conclusions
r e g a r d i n g n o n s a t u r a b i l i t y w e r e not justified.
A s i m i l a r c r i t i c i s m can
be applied to R e e v e ' s c o u n t e r - t r a n s p o r t e x p e r i m e n t , which also failed
to f a v o u r a t r a n s p o r t s y s t e m . Indeed as d e s c r i b e d in the n e x t s e c t i o n ,
evidence
h a s b e e n p r e s e n t e d t h a t amino acids m a y p e r m e a t e the
m e m b r a n e of l y s o s o m e s by a t r a n s p o r t process.
212
DOCHERTY ET AL.
Cystinosis
N e p h r o p a t h i c c y s t i n o s i s is a g e n e t i c a l l y d e t e r m i n e d disorder,
inherited in an autosomal recessive fashion and characterized by the
Fanconi syndrome and progressive renal failure.
The leucocytes and
fibroblasts of such patients contain 50-100 times the normal amount of
non-protein cystine (Schneider et al., 1967), which is contained within
the lysosomes (Schulman et a l , 1969).
The disorder can best be
explained as either a defect in the metabolic interconversions between
cystine and (the smaller and therefore more permeable) cysteine, or
as a defect in the permeability of the lysosomal membrane to cystine.
In order to t e s t the l a t t e r t h e o r y , l y s o s o m e s from leucocytes
(Steinhertz et al., 1982; Gahl et al., 1982a), transformed lymphoblasts
(3onas et al., 1982a), and f i b r o b l a s t s (Jonas et al., 1982b) of
cystinotic patients were loaded with 355-cystine and the rate of efflux
compared with that in lysosomes from normal patients. The lysosomes
were loaded with cystine using the mixed disulphide of cysteine and
glutathione or using cystine methyl ester. Despite an initial report to
t h e c o n t r a r y (Steinhertz et a l , 1982), the efflux of cystine was
c o n s i d e r a b l y slower in the lysosomes from cystinotlc cells than in
those from normal ceils (Gahl et a l , 1982a; Jonas et a l , 1982a).
The efflux of cystine was enhanced by ATP, which suggested to 3onas
et al. (1982b) that it may be dependent upon the functioning of a
lysosomal proton pump.
Gahl et al (1982b) demonstrated that the
efflux of cystine from lysosomes from leucocytes of normal patients
was not only stimulated by ATP, but also demonstrated saturability,
thus i n d i c a t i n g the presence of a cystine-transport system in the
tysosomal membrane. Lysosomes from leucocytes of cystinotic patients
exhibited no transport of cystine, while the lysosomes from leucocytes
of individuals heterozygous for cystinosis exhibited half the normal
rate of cystine transport. These observations are consistent with the
hypothesis that the disorder cystinosis is caused by a defect in the
transport of cystine across the lysosomal membrane.
The Lysosomal-Membrane Proton Pump
Two different mechanisms have been proposed for the maintenance
of the acidic interior of lysosomes. The proton gradient is thought to
be m a i n t a i n e d either by a Gibbs-Donnan-type equilibrium, whereby
fixed or impermeable acidic molecules within the lysosome buffer the
pH within a certain range, or by an energy-dependent proton pump
located in the lysosomal membrane. Evidence for the maintenance of
t h e acidic e n v i r o n m e n t within the l y s o s o m e by a Gibbs-Donnan
e q u i l i b r i u m is based on studies on the permeability of lysosomal
m e m b r a n e s to ions~ which d e m o n s t r a t e d that the membrane was
permeable to protons and monovalent cations (Goldman & Rottenberg,
1973; Henning, 1975). However, these experiments were performed at
about 4~
but at more physiological temperatures (25~
and 37~
the lysosomal membrane was found to be impermeable to monovalent
cations.
It was then suggested that the Gibbs-Donnan equilibrium
involved movement of protons with a charge compensatory movement
of anions (Reijngoud & Tager, 1975).
E v i d e n c e for a lysosomal-membrane proton pump was originally
based on the observation that added ATP stimulated proteolysis in the
PERMEABILITY PROPERTIES OF LYSOSOMAL MEMBRANES
213
lysosome (Mego et al., 1972). Since then lysosomal membrane ATPase
activity has been reported (Schneider, 1974; 1977; Titani & Wells,
1974), and ATP-dependent enhancement of methylamine (Schneider,
1979) and acridine orange (Dell'Antone, 1979) uptake into lysosomes
has also been reported. These latter uptake experiments have come in
:[or criticism however (Holemans et ai., 19g0), on the grounds that the
ATP e f f e c t was non-specific or that the ATP-dependent process was
due to impurities in the lysosomal preparation.
Recent convincing
evidence for a lysosomal proton pump comes from experiments using
fluorescein isothiocyanate-dextran, which is phagocytosed by cells and
accumulates in the lysosome.
The fluorescence of this compound is
sensitive to changes in pH.
Thus, intact ceils (Ohkuma and Poole,
1978), or isolated lysosomes (Ohkuma et al., 1982) loaded with the
reagent were placed in a spectrofluorimeter, and the e f f e c t of various
additions on the intralysosomal pH recorded. In the presence of Mg2+,
the addition of ATP caused acidification of the isolated lysosomes.
T h i s was r e v e r s e d
by t h e p r o t o n o p h o r e
carbonyl
cyanide
p - t r i f l u o r o m e t h o x y p h e n y l h y d r a z o n e , suggesting the presence of an
electrogenic ATP-driven proton pump (Ohkuma et al., 1982).
The
electrogenic nature of this proton pump is in disagreement with the
observations of Schneider (1981) from methylamine-uptake experiments
that suggested that the proton pump was electroneutral.
Conclusions
The properties of sugar entry into lysosomes satisfy all the criteria
which have been tested of a facilitated diffusion transport system
(Stein, 1967).
This lysosomal transport system, which appears to be
similar to that in the plasma membrane, can arrive at its destination
in the lysosome d i r e c t l y via the r o u g h - e n d o p l a s m i c - r e t i c u l u m /
Golgi-apparatus route, or it may be derived from the plasma
membrane during endocytosis.
Recent work has indicated that
elements of the plasma membrane are indeed in dynamic equilibrium
with intracelJular counterparts (Schneider et al., 1979; Stanley et al.,
1980; Widnell et al., 1982).
It is not at present clear whether the
sugar-transport system is present in the primary ]ysosome.
If the
t r a n s p o r t e r was present only in secondary lysosomes, it could be
concluded that the system was derived from the plasma membrane, but
until a preparation consisting exclusively of primary lysosomes can be
purified, this question cannot be answered definitively.
Whether the lysosomaJ sugar transporter is regulated is not known.
Regulation of fat-cell glucose transport appears to be effected not by
an activation of pre-existing transporters, but by movement of an
intracellular pool of transporters to the cell surface (Suzuki & Kono,
1980; Cushman & Wardzala, t9g0).
It is possible that the lysosomal
glucose-transport system is part of this intracellular pool. An effect
of ions on the uptake of sugars into rat liver lysosomes, as measured
by t h e osmotic protection method, has been observed (Docherty &
Hales, 1979).
Whether this has any role in regulating the lysosomal
sugar-transport system is not clear.
A review of the literature on the permeability of lysosomes to
amino acids and peptides does not at present allow one to conclude
whether transport systems exist. Only in the case of cystine (Gah] et
214
DOCHERTY
ET AL.
al., 1982b) has a transport system clearly been demonstrated.
This
lysosomal cystine-transport system is similar to that of the plasma
membrane, at least in so far as it is energy dependent (Rosenberg &
Downing, 1965).
Schulman et al. (1971) demonstrated that the rate
Of uptake of [35S]cystine into leucocytes from cystinotic patients was
the same as into those from normal patients. These authors, however,
did not provide any k i n e t i c evidence that they were studying a
transport process.
If in cystinosis the cystine transport system is
absent from the lysosome (Gahl et al., 1982b) while present in the
plasma membrane, this may be taken as evidence that the transport
system of lysosomes is not derived from or the same as that of the
plasma membrane.
Alternatively, the abnormality in cystinosis could
be a defect in the mechanism whereby the plasma-membrane transport
system is translocated from the plasma membrane to the lysosome (J.
P. Luzio7 p e r s o n a l c o m m u n i c a t i o n ) .
Some instances of familial
hypercholesterolaemia provide a precedent for such a change in which
t h e p a r t i c u l a r d e f e c t is in t h e mechanism whereby the plasmamembrane LDL receptor is internalized (Brown & Goldstein, 1979).
Evidence appears to favour the existence of a lysosomal proton
pump, and it is interesting that the electrogenic proton pump described
by Ohkuma et al. (1992) is more similar to the proton pump described
in the chromaffin granule (Njus et al., 19gl) and the insulin-secretory
granule (Hutton & Peshavaria, 1982) than to the mitochondrial proton
pump. This is in keeping with the predicted similarities between the
lysosome and the secretory granule as described by Hales (197g).
It is becoming clear that the membranes of the cellular organelles
involved in the processes of lysosomal degradation and of secretion are
not merely delimiting lipid bilayers, but contain functional integral
protein components.
E x a m p l e s of such components include the
s i g n a l - p e p t i d e - t r a n s l o c a t i n g a p p a r a t u s of the rough endoplasmic
r e t i c u l u m ( K r i e b i c h et al., 197g), the i n t r a c e l l u l a r mannose-6phosphate receptors involved in the transport of lysosomal enzymes to
their site of function (Gonzalez-Noriega et al., 19g0), and the proton
pumps of the chromaffin (Njus et al., 19gl) and the insulin-secretory
g r a n u l e ( H u t t o n & P e s h a v a r i a , 1992).
In this review we have
described the presence of such components in the lysosomal membrane.
It will be interesting to see what new lysosomal-membrane components
will be discovered. One candidate is a system for the specific uptake
of cytosolic proteins for degradation in the lysosome.
References
Berthet J, Berthet L 7 Applemans F & Duve C (1951) Biochem. J.
507 182-189.
Brown MS & Goldstein JL (1979) Proc. Natl. Acad. Sci. U.S.A.
767 3330-3337.
Cohn ZA & Ehrenreich BA (1969) J. Exp. Med. 129, 201-225.
Cushman SW & Wardzala LJ (1980) J. Biol. Chem. 2557 4758-4762.
Dell'Antone P (1979) Biochem. Biophys. Res. Commun. 867
180-189.
Docherty K & Hales CN (1979) FEBS Lett. 106, 145-148.
Docherty K & Hales CN (1980) Biochem. Soc. Trans. 8, 316.
Docherty K & Steiner DF (1982) Annu. Rev. Physiol. 447 625-638.
PERMEABILITY PROPERTIES OF LYSOSOMAL MEMBRANES
215
Docherty K, Brenchley GV & Hales CN (1979) Biochem. J. 178,
361-366.
Ehrenreich BA & Cohn ZA (1969) J. Exp. Med. 129, 227-243.
Elliott KRF & Craik JD (1982) Biochem. Soc. Trans. I0, 12-13.
Gahl WA, Tietze F~ Bashan N, Steinhertz R & Schulman JD (1982a)
J. Biol. Chem. 257, 9570-9578.
Gahl WA, Basham N, Bernardina I & Schulman JD (1982b) Science
217, 1263-1265.
Goldman R & Kaplan A (1973) Biochim. Biophys. Acta 318, 205-216
Goldman R & Rottenberg H (1973) FEBS Lett. 33, 233-238.
Gonzalez-Noriega A m Grubb JH, Talkard V & Sly WS (1980) J. Cell
Biol. 85, 839-852.
Hales CN (1978) FEBS Lett. 94, 10-16.
Hales CN & Docherty K (1979) in 'Proteases and Hormones' (Agarwal
MK 9 ed), pp 19-46, Elsevier/North Holland, Amsterdam.
Henning R (1975) Biochim. Biophys. Acta 401, 307-316.
Hollemans M 9 Donker-Koopman W & Tager JM (1980) Biochim. Biophys.
Acta 603, 171-177.
Hutton JC & Peshavaria M (1982) Biochem. J. 204, 161-170.
Jacobs MH (1934) J. Cell Comp. Physiol. 49 161-183.
Jonas AJ, Greene AA 9 Smith ML & Schneider JA (1982a) Proc. Natl.
Acad. Sci. U.S.A. 79, 4442-4445.
Jonas AJ 9 Smith ML & Schneider JA (1982b) J. Biol. Chem. 257,
13185-13188.
Joseph SK, Bradford NM & Megwan JD (1978) Biochem. J. 176,
827-836.
Kreibich G, Ulrich BL & Sabittini DD (1978) J. Cell Biol. 77,
464-487.
LeFevre PG (1961) Pharmacol. Rev. 13, 39-70.
Leighton F, Poole B~ Beufay H, Baudhuin P9 Coffey JW, Fowler S &
deDuve C (1968) J. Cell. Biol. 37, 482-513.
Lloyd JB (1969) Biochem. J. 115, 703-707.
Lloyd JB (1971) Biochem. J. 121, 245-248.
Maguire GA, Docherty K & Hales CN (1983) Biochem. J. 212,
211-218.
Mego JL, Farb RM & Barnes J (1972) Biochem. J. 128, 763-769.
Njus D 9 Knoth J & Zallakian M (1981) Curr. Top. Bioenerg. 11,
107-147.
Ohkuma S & Poole B (1978) Proc. Natl. Acad. Sci. U.S.A. 75,
3327-3333.
Ohkuma S, Monyama Y & Tokano T (1982) Proc. Natl. Acad. Sci.
U.S.A. 79, 2758-2762.
Perlman RL (1976) Biochem. Pharmacol. 25, 1035-1038.
Post RL, Morgan HE & Park CR (1971) J. Biol. Chem. 236,
269-272.
Reeves JP (1979) J. Biol. Chem. 254, 8914-8921.
Reijngoud DJ & Tager JM (1977) Biochim. Biophys. Acta 472,
419-449.
Reijngoud DJ & Tager JM (1975) FEBS Lett. 54, 76-79.
Rosenberg LE & Downing S (1965) J. Clin. Invest. (1965) 44,
1382-1393.
Schneider DL (1974) Biochem. Biophys. Res. Commun. 61~ 882-888.
Schneider DL (1977) Membrane Biol. 34, 247-261.
216
DOCHERTY
ET AL.
Schneider DL (1979) Biochem. Biophys. Res. Commun. 879 559-565.
Schneider DL (1981) J. Biol. Chem. 2569 3858-3864.
Schneider JA 9 Bradley KH & Seegmiller JD (1967) Science 157~
1321-1322.
Schneider YJ, Tulkens P9 deDuve C & Trouet A (1979) J. Cell.
Biol. 829 466-474.
Schulman JD~ Bradley KH & Seegmiller JD (1969) Science 166~
1152-1154.
Schulman JD9 Bradley KH 9 Berezesky IK 9 Grimley PM 9 Dodson WE &
AI-Aish MS (1971) Pediat. Res. 5, 501-510.
Stanley KK, Edwards MR & Luzio JP (1980) Biochem. J. 1869
59-69.
Stein WD (1967) in 'The Movement of Molecules Across Cell
Membranes' 9 pp 126-1769 Academic Press~ New York & London.
Steinhertz R~ Tietze F, Raiford D~ Gahl WA & Schulman JD (1982)
J. Biol. Chem. 257~ 6041-6049.
Suzuki K & Kono T (1980) Proc. Natl. Acad. Sci. U.S.A. 729
2542-2549.
Titani N & Wells WW (1974) Arch. Biochem. Biophys. 164,
357-366.
Trouet A (1974) Methods Enzymol. 31, 323-329.
White MD~ Kuhn NJ & Ward S (1980) Biochem. J. 190~ 621-624.
Whitesell RR & Gliemann J (1979) J. Biol. Chem. 2549 5276-5283.
Widnell CC9 Schneider YJ, Pierre B 9 Baudhuin P & Trouet A (1982)
Cell 28~ 61-70.