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Available online at www.sciencedirect.com
Peptide trafficking and translocation across membranes in
cellular signaling and self-defense strategies
Rupert Abele and Robert Tampé
Cells are metastable per se and a fine-tuned balance of de novo
protein synthesis and degradation shapes their proteome. The
primary function of peptides is to supply amino acids for de
novo protein synthesis or as an energy source during
starvation. Peptides are intrinsically short-lived and steadily
trimmed by an armada of intra and extracellular peptidases.
However, peptides acquired additional, more sophisticated
tasks already early in evolution. Here, we summarize current
knowledge on intracellular peptide trafficking and translocation
mediated by ATP-binding cassette (ABC) transport
machineries with a focus on the functions of protein
degradation products as important signaling molecules in
self-defense mechanisms.
Address
Institute of Biochemistry, Biocenter, Goethe University Frankfurt, Maxvon-Laue Str. 9, D-60438 Frankfurt a.M., Germany
Corresponding author: Tampé, Robert (tampe@em.uni-frankfurt.de)
Current Opinion in Cell Biology 2009, 21:1–8
This review comes from a themed issue on
Membranes and organelles
Edited by Greg Odorizzi and Peter Rehling
0955-0674/$ – see front matter
# 2009 Elsevier Ltd. All rights reserved.
DOI 10.1016/j.ceb.2009.04.008
pathway seems to be conserved in animal development to
guide tissue and organ formation. As very recently
demonstrated, Drosophila germ cell migration is spatiotemporally controlled by an ABC transporter secreting
lipid-modified peptides as germ cell attractant [2]. For
cell–cell communication, peptide hormones and neuropeptides have evolved as important signaling molecules
in metazoa. The processing of these peptides can occur
intracellularly or in extracellular milieu by specific
enzymes. Antimicrobial peptides synthesized by ribosomes are found in all phyla of life [3]. They are involved
in central defense strategies of innate immunity used by
invertebrates and vertebrates to combat infections. With
the development of an adaptive immune system in jawed
vertebrates, peptides are critically linked to the survival of
the organism as they are presented on the cell surface
bound to major histocompatibility complexes (MHC) for
the recognition and elimination of infected or malignantly
transformed cells.
Since the site of production of these peptides maybe far
from the destination where they fulfill their function,
sophisticated membrane translocation mechanisms have
evolved to ensure their correct compartmentalization. A
large fraction of peptides are generated in endosomal
compartments and secreted by the exocytic pathway.
In addition, transport machineries translocate peptides
across the plasma membrane. Cytosolic and mitochondrial degradation products are translocated by intracellular ABC transport machineries, which are in the focus of
this review.
Compartmentalization of peptides in
communication and self-defense
Translocation of proteasomal degradation
products across the ER membrane
Peptides are ubiquitous as short-lived intermediates
during protein breakdown to amino acids. Nonetheless,
already early in evolution, peptides gained additional
functions. In bacteria and fungi, non-ribosomally synthesized peptides evolved into an efficient self-defense system against competitors. Small peptides are also critically
involved in quorum sensing, in which they act as autoinducers to regulate bioluminescence, genetic competence, mating stress response, virulence expression, and
biofilm formation. In eukarya, peptides often act as signaling molecules. The mating a and a factors in yeast
represent a well-established example. While factor a is
secreted by the classical signal peptide-dependent
secretory pathway, factor a is exported by the ABC
transporter Ste6p after a series of post-translational
modifications [1]. The latter signal peptide-independent
Protein degradation is essential for various cellular processes ranging from cell cycle control, amino acid metabolism under starvation, to the removal of senescent and
often misfolded proteins as well as defective ribosomal
products (DRiPs). Protein degradation occurs mainly
either in lysosomal compartment, induced by autophagy
[4,5], or in the cytosol via the ubiquitin–proteasome
pathway. The 26S proteasome recognizes and disassembles polyubiquitinated proteins via the 19S cap structure
so that the 20S core complex can hydrolyze the target
protein to fragments ranging from 4 to 30 residues [6].
The degradation products are highly unstable with a halflife of a few seconds and are finally reduced to amino acids
by legions of endo- and exopeptidases. A minor fraction of
the proteasomal degradation products, preferentially
derived from DRiPs, are recognized and translocated into
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2 Membranes and organelles
Figure 1
Intracellular peptide trafficking and translocation. Degradation products of the ubiquitin–proteasome pathway or the mitochondrial quality control
system, surviving cytosolic peptidases, are shuttled by the TAP translocation machinery into the ER-lumen, where MHC I loading occurs. Alternatively,
polypeptides are delivered into lysosomes by the TAPL transport complex for putative loading of MHC II molecules. Further details are described in the
text.
the ER lumen for loading of MHC class I molecules by a
macromolecular translocation machinery, including the
transporter associated with antigen processing (TAP) as a
key component (Figure 1).
The TAP translocation complex belongs to the superfamily of ABC proteins and forms a heterodimer composed of TAP1 and TAP2 (Figure 2; see [7,8] for details
on TAP structure and function). Each half-transporter
contains a cytosolic nucleotide-binding domain (NBD),
which converts the chemical energy of ATP into conforCurrent Opinion in Cell Biology 2009, 21:1–8
mational changes to drive peptide translocation by the
transmembrane domain (TMD). The transmission interface between these domains is organized by extended
transmembrane helices, which are able to reach across and
contact the NBD of the opposite subunits by coupling
helices. This transmission interface plays an essential role
in peptide binding, signaling, and translocation [9,10].
The TMDs can further be dissected into a core region
consisting of the six C-terminal transmembrane helices
(TM) and a unique, extra N-terminal domain TMD0
composed of four TMs [11]. Remarkably, the core
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Peptide trafficking and translocation across membranes Abele and Tampé 3
Figure 2
Assembly and disassembly of the peptide-loading complex at the ER membrane. De novo synthesized MHC I heavy chain (hc) initially assembles with
the chaperones and ER-resident lectin calnexin. After association with b2m, calnexin is replaced by its soluble counterpart calreticulin. This MHC I
subcomplex docks to tapasin-ERp57, which is recruited to the TAP translocation machinery by its unique, extra N-terminal domain TMD0. After
peptide loading, a peptide–MHC complex is released and can traffic to the cell surface for inspection by cytotoxic T-lymphocytes. X-ray structures of
tapasin-ERp57 (3F8U.pdb) [19] and MHC I (HLA-A*0201) (1DUY.pdb) [65] are shown in a cartoon style, whereas the putative structure of calreticulin,
modeled on its homolog calnexin (2JHN.pdb) [66] is depicted as a surface representation. Calreticulin binds to the N-glycan of MHC I and via its
proline-rich domain to ERp57. Structural and mechanistic details of the 3D model of the TAP transport complex are given in [9]. The extra, N-terminal
TMD0 (four-helix bundle) is shown as surface model and single TMs are schematically illustrated.
transport complex retains all key functions in respect of
binding and translocation of antigenic peptides, while the
TMD0 of each subunit serves as an interaction hub for
recruiting the ER-resident type-1 membrane glycoprotein tapasin and thus the assembly of the macromolecular MHC I peptide-loading complex (PLC) (Figure 2).
The tapasin-TAP stoichiometry has been controversially
discussed; reports vary from one to four [12–14]. So it
remains to be discovered how many tapasin molecules are
needed for PLC function.
The PLC represents a dynamic macromolecular machinery for the recognition, translocation, and loading of
cytosolic degradation products onto MHC I molecules
in the ER lumen [15–18]. Apart from linking the peptide
donor to the peptide acceptor, tapasin fulfills several
functions in the PLC. Tapasin stabilizes the TAP complex and binds ERp57 by an intermolecular disulfide
bridge. The tapasin-ERp57 dimer interacts with MHC
I via their ER-lumenal domains so that tapasin can edit
peptide epitopes loaded onto MHC I molecules. Based
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on a combination of structural studies and site-directed
mutagenesis, it has been proposed that tapasin interacts
mainly with the a2-1 helix of MHC I, thereby stabilizing
the peptide-binding groove in a more open conformation
[19]. Consequently, low affinity peptides will dissociate,
while high-affinity peptides promote the closure of the
MHC I binding pocket [20,21]. Once a kinetically
stable peptide–MHC complex has been formed, it dissociates from the loading machinery and traffics to the cell
surface for presenting the antigenic cargo to cytotoxic Tcells. How these essential processes of peptide recognition, translocation, and loading are spatiotemporally
synchronized within a single machinery remains to be
resolved by a combination of cell and structural biological
approaches. In addition, it is unclear how tapasin independent MHC I alleles select high affinity peptides.
Peptides transported by TAP range from 8 to 16 residues,
while the MHC I molecules bind peptides mainly from 8
to 10 residues in length. Notably, TAP and MHC I
molecules display the same specificity for the C-terminal
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4 Membranes and organelles
residue, but differ at the N-terminus of the peptides.
Hence, peptides must be N-terminally trimmed by the
ER-resident amino-peptidase ERAP1 to the adequate
length after translocation into the ER [22–24]. It has
been suggested that peptides are recognized by the Cterminal hydrophobic residue and the amino group at the
N-terminus of the elongated peptide and are processed
by a molecular ruler mechanism to 9-mer peptides.
determine, how the translocon and TAP machinery traffic to the phagosomal or endosomal compartment in
dendritic cells. Remarkably, forcing non-professional
antigen-presenting cells to phagocytose, turned those
to ERAD mediated cross-presentation competent cells
[36].
Based on the peptide stimulated ATP hydrolysis of TAP,
a transport rate of five peptides per second has been
estimated, which guarantees an instant supply of antigenic peptides during viral infection or malignant transformation [25]. Because of this efficient translocation, an
export mechanism must exist to prevent an overload of
peptides in the ER, which otherwise would interfere with
the ER folding machinery and thus induce unfolded
protein response (UPS) pathways. Most likely, the peptides leave the ER via the translocon as also proposed for
the ER-associated protein degradation (ERAD) pathway
[26–28].
Since the compartmentalization of antigens is an essential step in immune surveillance, infected and malignantly transformed cells exhibit sophisticated strategies
to interfere with peptide supply to MHC I molecules
[37,38]. Note worthily, inhibitors of the TAP translocation machinery have been identified in all subfamilies of
herpes viruses (Figure 3). The immediately early gene
product ICP47 (IE12) of herpes simplex virus 1 and 2
blocks peptide binding to TAP [39,40]. For high-affinity
inhibition, ICP47 is enriched at the ER membrane,
thereby inducing a helix-loop-helix conformation [41].
The early gene product US6 of human cytomegalovirus
represents an ER-resident type 1 membrane glycoprotein, which inhibits ATP binding to TAP in the
cytosol via its ER-lumenal domain [42,43]. In the presence of US6, peptides can bind to the TAP complex,
but ATP hydrolysis and peptide translocation is blocked.
By using human and rat TAP chimera, the interaction
sites of US6 have been mapped to ER-resident loops in
both subunits of TAP [44]. However, further comprehensive approaches are necessary to identify structural
rearrangements within TAP leading to this inhibition
effect on the opposite site of the membrane. More
recently, BLNF2a, expressed in the lytic phase of
Epstein-Barr virus (EBV), was discovered as a TAP
inhibitor [45]. Remarkably, this viral factor simultaneously blocks the peptide and ATP binding activity
of the TAP machinery. Conspicuously, although the
EBV protein does not contain a signal sequence, it is
localized to the ER membrane [46]. Based on its primary
structure, BLNF2a may represent a tail-anchored
protein, which is post-translationally inserted into the
membrane. Notwithstanding, the pathway of membrane
targeting, insertion, and topology as well as its inhibition
mechanism remains to be discovered.
Compartmentalization of peptides in antigen
cross-presentation
By studying professional antigen presenting cells
(pAPCs), such as dendritic cells, it became clear that
MHC I do not only presents endogenous but also exogenous antigens. This cross-presentation is essential for
priming of naı̈ve to cytotoxic T-cells at location remote
from the site of infection. Interestingly, the ERAD pathway seems to be also involved in cross-presentation in
pAPCs, in which exogenous particulate antigens are
taken up by phagocytosis and soluble antigens by receptor mediated endocytosis [29,30–33]. Interestingly,
phagosome acidification in dendritic cells is retarded so
that antigens are not immediately degraded by lysosomal
proteases but have the chance to reach the cytosol [34]. In
contrast, the fate of soluble antigens depends on the
receptor involved in endocytosis. Antigens taken up by
the mannose receptor mediated endocytosis are routed to
stable endosomes [35]. Degradation products of these
antigens are finally loaded onto MHC I molecules. In
contrast, soluble antigens taken up by pinocytosis or a
scavenger receptor are targeted rapidly to lysosomal
degradation for presentation on MHC II molecules
[35]. Subsequently, antigens are translocated from
the endosomal or phagosomal compartment to the cytosol for proteasomal degradation [30]. For phagosomes,
protein retrotranslocation by the translocon is assumed,
whereas the protein export path from endosomes is
unclear. After proteasomal degradation in the cytosol,
peptides are redirected into the phagosomes by the TAP
translocation machinery and loaded onto MHC class I
molecules, which then present their antigenic cargo on
the cell surface. Alternatively, these proteasomal degradation products can follow the classical MHC I pathway
starting in the ER [31]. It will be of particular interest to
Current Opinion in Cell Biology 2009, 21:1–8
Immune evasion strategies by blocking
peptide supply
Varicello viruses target the TAP complex by the type 1
transmembrane protein UL49.5 by using different strategies. In most cases, the TAP machinery is arrested in a
translocation incompetent conformation without affecting peptide binding. In addition to inhibition of peptide
translocation, UL49.5 from bovine herpes virus induces
proteasomal degradation of the TAP complex [47–49].
Apart from the viral strategies to escape immune surveillance by blocking peptide translocation into the ER,
tumor cells have also developed several ways to downregulate MHC I surface expression via interference with
TAP function [50].
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Peptide trafficking and translocation across membranes Abele and Tampé 5
Figure 3
Viral immune evasion mechanisms via the TAP translocation machinery. While ICP47 from herpes simplex virus blocks peptide binding to TAP, the
human cytomegaloviral protein US6 inhibits ATP binding via its ER-luminal domain. The varicelloviral protein UL49.5 arrests a translocation
incompetent conformation and induces proteasomal degradation via its C-terminal tip. BNLF2a from Epstein-Barr virus impedes peptide and ATP
binding.
Lysosomal polypeptide translocation
In non-stressed cells, short-lived and misfolded proteins
are degraded mainly by proteasomal activity. Alternatively, proteins are delivered into lysosomes for proteolysis by different modes of autophagy [4,5]. These latter
pathways are strongly upregulated under starvation or
oxidative stress. Autophagy diminishes the accumulation
of protein aggregates involved in neurodegenerative disease and plays an important role of loading cytosolic
antigens onto MHC II molecules in professional antigen
presenting cells. In micro- and macroautophagy, parts of
the cytosol are invaginated and subsequently degraded in
lysosomes. In contrast, chaperone-mediated autophagy is
a highly specialized process. In this case, long-lived or
oxidized proteins are recognized in complex with heatshock proteins and are shuttled into lysosomes with the
help of LAMP-2A [5]. Still neither the transport machinery nor the mechanism of polypeptide translocation has
been deciphered so far.
The ABC transport complex ABCB9 has been identified
as a lysosomal polypeptide transporter [51]. ABCB9,
which shows the highest sequence identity to TAP1
and TAP2, therefore called TAP-Like (TAPL), forms
a homodimer in the lysosomal membrane [51,52,53].
The phylogenetic relationship between these ABC
proteins is also reflected in the genome organization.
All three human genes comprise 11 coding exons with
almost identical lengths except for the flanking exons.
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Similar to TAP2, the TAPL gene displays a non-coding
exon at the 50 end and splice variants of the 30 -terminal
exon [54]. Since these splice variants lack important
motifs of the NBD, these gene products are predicted
to be inactive, but may take over a regulatory function by
association with functional TAPL subunits. Interestingly,
TAPL seems to be the common progenitor for all TAP
subunits since orthologs are found in vertebrates and
invertebrates and even in plants. Noticeably, the evolution rate of TAPL is much slower than for the TAP
subunits suggesting a more conserved function of this
transporter.
The function of TAPL is distinct from that of TAP as it is
unable to restore MHC I surface expression in TAP
deficient cell lines [53]. TAPL is expressed in different
tissues with highest expression found in testis, followed
by central nervous system and heart [52,55]. Strikingly,
TAPL expression is strongly upregulated during the
differentiation of monocytes into dendritic cells [53].
In analogy to the heterodimeric TAP complex, TAPL
also has an extra N-terminal membrane domain (TMD0),
which shows no sequence homology to any other protein.
It will be interesting to analyze whether this domain as
well is involved in recruiting interaction partners as
demonstrated for TAP.
In contrast to TAP, which recognizes peptides with a
length of 8–16 amino acids with high affinity, TAPL
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6 Membranes and organelles
shows a much broader length specificity ranging from 6mer up to 60-mer peptides [51]. Peptide selectivity is
restricted to the N-terminal and C-terminal residue,
where positively charged and large hydrophobic residues
are favored over negatively charged residues [56]. This
smaller contact site with the peptide as compared with
TAP, which includes also the second and third N-terminal residues for peptide binding, could explain the lower
peptide affinity of TAPL as compared to TAP. Although
the physiological function of TAPL still waits to be
illuminated, this transporter may function as a vacuum
cleaner to dispose peptides from the cytosol whenever the
cytosolic degradation machineries are overloaded. As it is
strongly upregulated in dendritic cells, TAPL could be
involved in the delivery of proteasomal degradation products for loading of MHC II molecules (Figure 1) [57].
This pathway is essential in the positive and negative
selection of T-cells in the thymus. Additionally, this
newly identified lysosomal translocation pathway could
turn out to be important in dendritic cells to induce an
MHC II dependent immune response against intracellular pathogens.
Mitochondrial quality control and peptide
export
Mitochondria harbor an elaborate quality control system,
including several machineries for degradation of proteins
to peptides and amino acids. Since peptides derived from
proteins, encoded by the mitochondrial genome, are
presented as minor antigens in complex with MHC I
molecules at the cell surface, a mitochondrial peptide
exporter has been postulated [58]. Approximately 30% of
the degraded proteins in yeast mitochondria are released
as peptides into the cytosol [59]. It has been speculated
that these peptides are involved in a mitochondria-tonucleus signaling pathway in respiring yeast [60]. In this
working model, peptides generated by the i-AAA
(ATPase associated with various cellular activities) protease in the intermembrane space can traverse the outer
membrane by porins. But peptides generated by the mAAA protease in the matrix must be actively transported
[59]. The homodimeric ABC transporter Mdl1p from
Saccharomyces cerevisiae was postulated as the peptide
transport machinery (Figure 1). In comparison to wild
type strains, DMDL1 mitochondria shows a reduced level
of released peptides in the range between 0.6 and
2.1 kDa. Overexpression of Mdl1p in MDL1-deletion
cells compensated for this defect [59]. Notably, highcopy expression of Mdl1p or its human ortholog ABCB10
partially restores the drastic phenotype deleting the homologous mitochondrial ABC transporter Atm1p, which
plays an essential role in the maturation of cytosolic
iron-sulfur cluster proteins [61–63]. This implies that
Atm1p (ABCB7 in human) and Mdl1p (ABCB10 in
human) have overlapping functions. These ABC systems
may translocate peptidic compounds, which directly or
indirectly act as precursors or factors essential for the
Current Opinion in Cell Biology 2009, 21:1–8
maturation of cytosolic iron–sulfur cluster proteins [64].
Nevertheless, all attempts to identify the physiological
substrate of these mitochondrial ABC transport systems
were unsuccessful [64].
Conclusions and future perspectives
Quite early in evolution, transient products of protein
breakdown have been used as signaling molecules between cells. In eukaryotes, peptides are shuttled also
across intracellular membranes, culminating in the antigen presentation pathway of the adaptive immune system
in higher vertebrates. Although the function of the antigen translocation machinery TAP in antigen presentation
is elucidated, there are numerous unresolved questions.
On a molecular level, the transport and viral inhibition
mechanisms of this translocation complex are a hot topic
of research. Because the TAP machinery is readily amenable to a very broad range of experimental approaches, it
has been proven to be an excellent model for ABC
transporters. Additionally, the dynamic assembly and
disassembly of the macromolecular MHC I peptide-loading complex need to be illuminated. Furthermore, the ER
retention mechanism and trafficking to the endosomal/
phagosomal compartments of the TAP machinery must
be resolved to understand the cell biology of cross-presentation in dendritic cells. For the other two intracellular
peptide ABC transporters found in mitochondria and
lysosomes, the elucidation of the physiological function
has to be the main focus and will maybe open new ideas
and insights in cell biology.
Acknowledgements
We thank lab members for discussions and advice. The work has been
supported by the Center for Membrane Proteomics (CMP), Cluster of
Excellence Frankfurt – Macromolecular Complexes, and the SFB 807 –
Membrane Transport and Communication of the German Research
Foundation. We apologize to all those colleagues whose important work is
not cited because of space considerations.
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