Originally published In Press as doi:10.1074/jbc.R100068200 on March 21, 2002
J. Biol. Chem., Vol. 277, Issue 20, 17377-17380, May 17, 2002
MINIREVIEW
Complexity in the Secretory Pathway: The Assembly and
Secretion of Apolipoprotein B-containing Lipoproteins*
Edward A.
Fisher
§ and
Henry N.
Ginsberg§¶
From the Cardiovascular Institute and Departments
of Medicine and Biochemistry, Mount Sinai School of Medicine, New York,
New York 10029 and ¶ Department of Medicine, Columbia University
College of Physicians and Surgeons, New York, New York 10032
 |
INTRODUCTION |
Apolipoprotein B100 (apoB100) is expressed
primarily in mammalian liver. It has 4536 amino acids, 25 cysteines (16 of which are in intramolecular disulfide bonds), and 20 N-linked glycosylation sites. A smaller form, apoB48, is
expressed in mammalian intestine and in the livers of some non-human
mammals. ApoB48 results from a post-transcriptional modification of the
apoB mRNA at codon 2153 that converts a glutamine codon to a stop
codon at ~48% of the full-length coding sequence. Both forms of apoB
have a complex structure that includes a globular amphipathic
NH2 domain spanning the first 15-20% (using B100 as a
standard length) of the polypeptide followed by an extended hydrophobic
-sheet domain from about 20 to 48%. In apoB100, the rest of the
polypeptide is comprised of an 
-helical amphipathic region, another
long -sheet domain, and another -helical domain.
In humans, apoB100 is an essential component of liver-derived very low
density lipoproteins (VLDL)1
and low density lipoproteins (LDL), whereas apoB48 is essential for the
formation of chylomicrons in the small intestine. VLDL, LDL, and
chylomicrons transport the majority of cholesterol and triglyceride
(TG) in the circulation of humans, and because increased plasma levels
of these lipoproteins are associated with increased risk for the
development of atherosclerosis, regulation of their assembly and
secretion is of considerable interest.
In this review, we summarize how this large, complex protein assembles
together with lipid molecules to form lipoprotein particles that are
then secreted. We emphasize the post-transcriptional regulation of
hepatic apoB lipoprotein formation and in particular, the
regulated intracellular degradation of apoB (for a recent review of the
transcriptional regulation of the apoB gene, see Ref. 1).
| |
Regulated Translation of ApoB |
Two studies have shown regulation at the level of elongation. The
first focused on rats made diabetic by injection of streptozotocin. Their primary hepatocytes exhibited a profound decrease in apoB synthesis with no change in apoB mRNA abundance (2). Using ribosomal transit time analysis, it was shown that the decreased synthesis could be explained by a prolonged elongation rate for apoB.
The second example is the report that the elongation of apoB mRNA
in HepG2 cells slows when translocation of nascent apoB across the
endoplasmic reticulum (ER) is inhibited by preventing microsomal
triglyceride transfer protein (MTP)-associated transfer of lipids to
the nascent polypeptide (3). The molecular mechanisms responsible for
the slowing of apoB translation in either study are not known but may
be related to unusual physical properties of hepatic polysomes
containing apoB mRNA (4).
| |
Regulation of ApoB Targeting to ER by the Signal Peptide |
ApoB is unusual in that there is common sequence variation in the
human population of the signal peptide (SP) (5). The "wild type" SP
is 27 amino acids long (SP27); a commonly occurring variant is 24 amino
acids long (SP24) and is the result of deletion of Leu-Ala-Leu
residues. This occurs at a carrier frequency of about 30% in
Caucasians, 21% in Blacks, and 19% in Chinese. Loss of Leu-Ala-Leu
may reduce the efficiency of insertion of the apoB SP into the ER (6),
consistent with the secretion in yeast of a fusion protein consisting
of apoB SP and invertase differing between the SP24 and SP27 versions
(7). Population studies, however, have not shown consistent
associations between the two polymorphisms and plasma lipid levels.
| |
The Bitopic Orientation of ApoB across the ER Membrane |
Most secretory proteins undergo efficient co-translational
translocation into the lumen of the ER (8, 9). Starting in the early
1990s, evidence accumulated that the translocation of apoB may not
conform to the classic paradigm (10). For example, in isolated
microsomes, domains of apoB were digested by exogenous proteases,
suggesting that apoB was exposed to the cytosol at some point(s) during
synthesis or intracellular transport. Although apoB does not have a
classical transmembrane domain, studies confirmed a "bitopic"
orientation in which there is simultaneous exposure of apoB domains to
the ER lumen and the cytosol (11-13). One basis for the bitopic
topology of apoB was suggested by studies in a cell-free system in
which putative "pause-transfer" sequences interrupted apoB
translocation but not translation (14). An alternative view of
translocational pausing proposes transient difficulties posed by the
secondary structure of apoB mRNA (15). Regardless of the exact
molecular bases, inefficient translocation, together with continued
translation, could result in the escape of the nascent polypeptide from
the translocon into the cytosol (16). Of interest, then, are recent
studies that have identified lateral openings between the ribosome and
the translocon that could provide an entrance into the cytosol for
nascent polypeptide chains (17, 18).
Yet another basis for inefficient translocation is the demonstration
that the presence of a portion of the first -sheet domain is
sufficient to cause exposure of nascent apoB to the cytosol (19). The
-sheet domain also made apoB secretion responsive to the presence of
oleic acid in the medium and dependent on MTP activity. Of note,
sequences containing numerous pause-transfer sequences, but lacking a
-sheet domain, were efficiently translocated and not exposed to the cytosol.
ApoB has a prolonged interaction with translocon-associated proteins
(20), and completion of translation may be delayed until a
lipid-associated signal for secretion occurs (21). The exact nature of
the interaction between -sheet domains of apoB and the translocon is
undefined, but it does provide a potential mechanism for regulation of
translocation by lipid availability.
As noted, MTP activity is required for apoB lipoprotein assembly and
secretion. MTP is a heterodimer consisting of protein-disulfide isomerase and a 97-kDa large subunit that transfers neutral lipids between membranes. Mutations in the gene encoding the large subunit are
the basis for the human syndrome, abetalipoproteinemia, in which
neither intestinal nor hepatic apoB lipoproteins are found in the
plasma (22). In addition to its involvement in the translocation of
-sheet-containing apoB molecules (see above), MTP has also been
shown to bind to two sites at the N-terminal end of apoB (24-28). One
binding site is within the first 5-6% of the N-terminal end whereas
the second is within the first 10% of the polypeptide. These
interactions may function in two early but crucial roles for MTP.
First, as a chaperone-like molecule, its binding to the distal N
terminus of apoB may be required for the initiation of translocation
(29-33). Second, MTP initiates lipid transfer upon binding to apoB,
and the co-translational addition of lipid to nascent apoB is necessary
to direct apoB away from early proteasomal degradation and toward
secretion (34-37). MTP may also play a role in the later stages of
maturation of the apoB lipoproteins as will be discussed below.
Exposure of apoB, particularly of hydrophobic domains in the protein,
to the cytosolic side of the ER may require an association with
cytosolic chaperones to prevent self-aggregation (and possibly cellular
toxicity) or to maintain secretion competency. For example, there
appears to be a functional interaction between apoB and cytosolic heat
shock protein 70 (hsp70) (34, 38, 39), when secretion was stimulated by
increased lipid availability, binding of apoB to hsp70 was reduced, and
when secretion was inhibited, binding of apoB (and its
ubiquitinylation) increased. These studies indicate that apoB exists,
at least transiently, in a bitopic topology that confers an opportunity
for cytosolic factors, such as molecular chaperones and components of
the ubiquitin (Ub)-proteasome pathway to interact with the molecule.
| |
Regulated Co- and Post-translational Degradation of ApoB |
Early pulse-chase studies in HepG2 cells (40) and in rat primary
hepatocytes (41) showed that a significant amount of newly synthesized
apoB is degraded. A number of laboratories over the past 10 years has
shown that this degradation is accomplished by both proteasomal and
non-proteasomal pathways and that each type of degradation is regulated
by one or more metabolic factors.
Proteasomal Degradation of ApoB--
Studies of apoB degradation
in HepG2 cells indicated that the turnover of the protein was rapidly
and negatively regulated by triglyceride synthesis. By applying
specific inhibitors of the proteasome (42-44), it was found that when
conditions are not favorable for apoB assembly with lipids, apoB is
ubiquitinylated and degraded by the proteasome (35, 45, 46). This
degradation involves the chymotrypsin-like activity of the
proteasome2 in a process
facilitated by cytosolic chaperones (hsp70, hsp90) that begins
co-translationally (34, 35, 39, 46). In contrast to ER-associated
degradation (ERAD) of other proteins (47) targeting of apoB was not
regulated by a mutation in its primary amino acid sequence. The lack of
co-translational lipidation leads to the targeting of the nascent, apoB
polypeptide to quality control mechanisms designed to prevent the ER
exit of misfolded proteins (48).
The route by which apoB enters the Ub-proteasome pathway has been
investigated. A commonly accepted model for ERAD substrates was full translocation into the ER, followed by retrotranslocation ("dislocation") back to the cytosol (49-51). Indeed, additional work suggests that unique sequences within the major translocon protein, sec61, are required for dislocation of certain abnormal proteins (52, 53).
Although there are some data consistent with a
translocation-retrotranslocation model (54), the bulk of evidence
favors an alternative model (Fig.
1A) in which apoB is targeted
co-translationally for degradation while it remains bound to the
ribosome and becomes engaged by cytosolic factors that lead to its
extraction from the translocon into the Ub-proteasome pathway (20, 21,
34, 55, 56). The level of degradation of apoB by the proteasome is
regulated by a number of metabolic factors. As noted above, a lack of
triglyceride synthesis or MTP activity increases apoB ERAD. Although
the supply of exogenous fatty acids influences triglyceride synthesis
in cultured cells, SREPB1-c-regulated lipogenesis also seems to be
important in protecting apoB from proteasomal degradation (57). Besides
hsp70, hsp90 can be a factor in the ERAD process (e.g. Refs.
58 and 59). Recently, it was found to promote apoB degradation by
the Ub-proteasome pathway (39) at a step distal to the effects of
hsp70. It has been proposed that one role of hsp90 in proteasome
function is to facilitate unfolding of the "doomed" substrates into
the narrow mouth of the 19 S cap (60). We have included this concept in
the scheme shown in Fig. 1A for the route and associated
molecular factors that come into play when apoB is unable to associate
with sufficient lipid ligands. Implicit in this model is that under
these conditions, many apoB polypeptides do not complete
translocation.
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Fig. 1.
Lipid ligand availability and apoB metabolism
in liver cells. A, when lipid ligands are limiting,
translocation is impeded by the lack of co-translational association of
lipids with -sheet regions, resulting in increased cytosolic
exposure of apoB domains to components of the Ub-proteasome pathway.
Based on studies of apoB and other ERAD substrates, a simple model is
that hsp70 promotes the extraction from the ER and the ubiquitinylation
of apoB, and hsp90 participates in a step distal to these events,
perhaps by facilitating the unfolding of apoB into the 26 S proteasome.
B, when lipid ligands are not limiting, after
co-translational and MTP-dependent assembly of lipid-poor
apoB lipoprotein, several pathways for maturation and lipid enrichment
of the particle are possible. 1, the lipid-poor apoB
lipoprotein enters the secretory pathway and is either secreted
unchanged (in rodent liver) or is enriched with core lipids in either
the vesicular tubular complex (VTC) or the Golgi prior to
secretion; 2, gradual lipid enrichment of the particle
occurs in the ER, and a mature, lipid-rich apoB lipoprotein traverses
the vesicular tubular complex and Golgi and is secreted; 3,
the lipid-poor apoB lipoprotein "fuses" with a preformed lipid
droplet in the ER, and the resultant lipid-rich apoB lipoprotein
continues along the secretory pathway. The fusion step appears to be
independent of MTP activity or lipid synthesis.
|
|
Non-proteasomal Degradation of ApoB--
The induction of apoB
degradation in rat primary hepatocytes by n-3 fatty acids
(found mainly in certain fish oils) and insulin are examples of a
non-proteasomal pathway. These metabolic perturbations stimulate a
process that not only degrades apoB but preferentially decreases the
secretion of the most buoyant apoB lipoproteins (61-63). Proteasomal
inhibitors do not affect apoB degradation stimulated by either fish
oils or insulin (61).3 A
variety of experimental data indicate that these stimuli induce the
degradation of apoB after translocation, assembly with lipids, and exit
from the ER (61, 64). Interestingly, inhibition of phosphatidylinositol 3-kinase reduces the degradation stimulated by either fish oils or insulin (61, 65), making it tempting to
speculate that overproduction of hepatic apoB lipoproteins in the
insulin-resistant state reflects decreased activity of this degradation
pathway. Other examples of apoB degradation that appear to occur
post-ER include regulation by choline deficiency (66), dexamethasone
(67), and the interaction of newly assembled apoB lipoproteins with LDL
receptors in the secretory pathway or at the cell surface (61, 68, 69).
In the latter case, cell surface heparin sulfate proteoglycans may also
serve an LDL receptor-like function.
There are also data suggesting intra-ER degradation of apoB (30,
70-73). Of note, in three of these studies, dithiothreitol inhibited
the degradation. In addition to a dithiothreitol-sensitive protease,
another candidate is ER-60, which has been shown to have serine
protease activity (74) and to interact with apoB in HepG2 cells (75).
However, there are no reports that inhibitors that decrease the
proteolytic activity of ER-60 increase apoB recovery. An alternative
role for ER-60 is that it may act as an ER chaperone for apoB, as it
does for other proteins (e.g. see Ref. 76).
Overall, the data support the occurrence of non-proteasomal apoB
degradation, but much remains to be determined, including the number of
distinct processes, the factors targeting apoB to this pathway, and the
proteolytic activities involved.
| |
Regulated Lipoprotein Assembly in the ER |
Little is known about how the mature, TG-enriched lipoprotein is
assembled, particularly the process of bulk lipid addition, the site
where that addition occurs, and the role of MTP in the final stages of
maturation. There are data (21) consistent with either the complete (or
nearly complete) formation of a TG-rich apoB lipoprotein while the
complex is still associated with the translocon or the formation of a
TG-poor particle at the translocon and rapid conversion to an apoB
VLDL. This latter possibility would be consistent with an early study
(77), which suggested that a lipid-poor form of apoB present in
the rough ER could "fuse" with lipid droplets in the smooth ER, as
well as with more recent studies (37, 78-83).
The further lipidation of the TG-poor, dense, apoB lipoprotein may
require its lateral diffusion to a specialized compartment of the ER or
transport to a pre-Golgi compartment (37, 80). MTP activity must be
present preceding and during the early stages of apoB lipoprotein
formation to have bulk lipid addition occur at a later stage (36, 84,
85). Thus, MTP may provide bulk lipid to the site where it is finally
added (86, 87). Alternatively, the addition of bulk lipid during the
later stages of assembly may be independent of MTP activity and ongoing
TG synthesis (20, 79, 83, 84, 88), suggesting that oleic acid, besides
stimulating core lipid synthesis, acts as a signaling molecule that
targets lipoproteins to the site of bulk lipid addition.
Small GTP-binding proteins and phospholipase D may function in the
later stages of apoB lipoprotein assembly (89). Palmitoylation of apoB
may target the protein to where bulk lipid addition can occur (90). The
possibility that oleic acid works together with phospholipase
A2 to generate oleoyl-enriched ER membrane phospholipids that stimulate movement of a lipid droplet into the ER lumen was also
raised recently (91). Whether n-3 fatty acids and insulin decrease or apoE increases VLDL secretion (64, 65, 93-96) by inhibition or stimulation, respectively, of the later steps of apoB
lipoprotein formation remains to be determined.
| |
Role of the Golgi in Lipoprotein Assembly |
There are studies that suggest that the final maturation of the
lipid-enriched apoB lipoprotein occurs in the Golgi (97-100). For
example, Golgi lipoproteins were of the size of VLDL, whereas those in
the ER were smaller (101). In other studies, the size ranges of Golgi-
and ER-derived rat hepatic apoB lipoproteins were similar (102), but
the larger size of secreted particles implied lipids had been added in
the Golgi (103). Potential restraints in the ER export processes (104)
may be avoided if full lipid loading occurred after leaving the ER. We
have incorporated some of the possible places of the assembly of apoB
with lipids as shown in Fig. 1B.
| |
Physiological Relevance of the Regulation of ApoB Lipoprotein
Assembly and Secretion |
Examples in humans likely to involve post-transcriptional
regulation of apoB include: 1) those with combined hyperlipidemia (105)
or the insulin resistance syndrome (106) who have increased hepatic
apoB lipoprotein secretion; 2) settings in which increased fatty acid
flux to the liver increases apoB secretion in VLDL (e.g.
Ref. 107); and 3) the reports that hyperinsulinemia can acutely inhibit
VLDL apoB secretion in normal subjects (but not in obese
insulin-resistant subjects) (108).
Of particular note is the recent report that HIV protease inhibitors,
agents that cause a dyslipidemia characterized by increased VLDL levels
(109), are inhibitors of the proteasome (110). In a variety of human
and rodent hepatic cell types treated with HIV protease inhibitors,
there was increased protection of nascent apoB from degradation and, in
the presence of oleic acid, increased secretion of apoB lipoproteins
(111). These data support a significant role for proteasomal
degradation in the in vivo regulation of apoB secretion in mammals.
There are also animal models of post-transcriptional regulation of apoB
secretion. For example, hamsters fed a high fructose diet had increased
assembly and secretion of VLDL apoB with no change in apoB mRNA
levels but with decreased non-proteasomal degradation of apoB (112).
There is also post-transcriptional regulation of apoB secretion in
human apoB transgenic mice lacking brown adipose tissue (92). Insulin
resistance was present in both of these animal models, underscoring the
relevance to the data obtained in humans.
| |
Summary |
ApoB is essential for the production of hepatic atherogenic
lipoproteins. The major role of post-transcriptional degradation of
apoB is surprising. The same lipophilic sequences enabling apoB to
partake in lipoprotein formation also appear to participate in its
targeting to proteasomal degradation when lipid export by the liver is
not favored. Even after the translocation of nascent apoB is completed,
several quality controls appear to be in place to further regulate
lipoprotein secretion. Indeed, the cellular "bureaucracy" developed
to regulate apoB lipoprotein assembly and secretion matches the
complexity of the lipoprotein itself.
| |
FOOTNOTES |
*
This minireview will be reprinted
in the 2002 Minireview Compendium, which
will be available in December, 2002. The work mentioned in this minireview was supported
by National Institutes of Health Grants HL 58541 (to E. A. F.) and HL
55638 (to H. N. G.).
§
Correspondence may be addressed to either author. E-mail:
edward.fisher@mssm.edu or hng1{at}columbia.edu.
Published, JBC Papers in Press, March 21, 2002, DOI 10.1074/jbc.R100068200
2
C. Cardozo, X. Wu, and E. Fisher, unpublished data.
3
J. Sparks, personal communication.
| |
ABBREVIATIONS |
The abbreviations used are:
VLDL, very low
density lipoprotein(s);
LDL, low density lipoprotein(s);
TG, triglyceride;
ER, endoplasmic reticulum;
MTP, microsomal triglyceride
transfer protein;
SP, signal peptide;
Ub, ubiquitin;
ERAD, ER-associated degradation;
HIV, human immunodeficiency virus.
| |
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INTRODUCTION
Regulated Translation of ApoB