Biol. Chem. 2015; 396(9-10): 967–974

Review Tina Zollmann, Christoph Bock, Philipp Graab and Rupert Abele*

Team work at its best – TAPL and its two domains Abstract: The transporter associated with antigen processing (TAPL, ABCB9) is a homodimeric ABC transporter, shuttling cytosolic polypeptides into the lumen of lysosomes energized by ATP hydrolysis. Here we give a short overview of the superfamily of ABC transporters and summarize the current state of knowledge on TAPL in detail. The architecture of TAPL and its substrate specificity are described and we discuss the function of an extra N-terminal transmembrane domain, called TMD0, in respect of subcellular targeting and interaction with proteins, contributing to long-term stability. As TAPL shows – besides a ubiquitous basal expression – an elevated expression in antigen presenting cells, we present models of TAPL function in adaptive immunity. Keywords: ABC transporter; adaptive immunity; LAMP; lysosome; peptide translocation; subcellular trafficking. DOI 10.1515/hsz-2014-0319 Received December 23, 2014; accepted February 20, 2015; p ­ reviously published online February 25, 2015

Introduction ATP-binding cassette proteins represent a large protein superfamily found in each organism. Common to all members of this family is a nucleotide binding domain (NBD), which dimerizes in the presence of ATP (Schmitt and Tampé, 2002). Some of the proteins are soluble factors involved in DNA repair and translation initiation, elongation, and termination as well as ribosome splitting and recycling (Davidson et  al., 2008; Nürenberg and Tampé, 2013). The vast majority of the ABC family members constitutes integral membrane proteins utilizing the energy of *Corresponding author: Rupert Abele, Institute of Biochemistry, Biocenter, Goethe University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt/Main, Germany, e-mail: [email protected] Tina Zollmann, Christoph Bock and Philipp Graab: Institute of Biochemistry, Biocenter, Goethe University Frankfurt, Max-vonLaue-Str. 9, D-60438 Frankfurt/Main, Germany

ATP hydrolysis to translocate allocrites across biological membranes (Dean, 2005). In prokaryotes, ABC importers accumulate nutrients such as amino acids, sugars, metal oxides, and vitamins in the cytosol, whereas exporters in prokaryotes and eukaryotes expel polysaccharides, toxins, lipids, peptides, and proteases out of the cytosol (Cui and Davidson, 2011). However, the strict distinction that only prokaryotes comprise ABC importers, does not hold anymore, as different ABC import systems in guard cells of leafs are described and there is strong evidence that human ABCA4 translocates retinal from the lumen of discs of the photoreceptor into the cytosol (Lee et al., 2008; Kang et  al., 2010; Sun, 2012). ABC exporters in human function as regulators, chloride channels, and transporters, which take over different cellular functions in cell homeostasis and adaptive immunity. Therefore, several diseases are linked to ABC transporter malfunction like cystic fibrosis, Stargardt’s disease, Tangier disease or bare lymphocyte syndrome (Borst and Elferink, 2002; Tarling et  al., 2013). Moreover, upregulation of multidrug transporter expression is involved in drug resistance in chemotherapy (Chen and Tiwari, 2011). Common to all ABC transporters is a core architecture composed of two transmembrane domains (TMDs) and two NBDs (ter Beek et al., 2014). The TMDs together form the translocation pathway and, in case of exporters, the allocrite binding site. Binding of ATP to the NBDs induces their dimerization, which causes conformational changes in the TMDs from the inward to the outward-facing conformation, transmitted by coupling helices, resulting in the translocation of the solute across the membrane. Afterwards, ATP hydrolysis is used to reset the transporter for the next transport cycle (Parcej and Tampé, 2010; George and Jones, 2012). Based on structure, ABC transporters are classified in four different groups (Locher, 2009; Rice et al., 2014). Type 1 and 2 importers contain an additional periplasmic binding protein, which delivers the solute by binding to periplasmic loops in the transmembrane domain of the transporter. Type 1 importers, for example molybdate/tungstate transporter ModBC from Archaeglobus fulgidus or the maltose transporter from Escherichia coli, contain generally a core of 10 transmembrane helices

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968      T. Zollmann et al.: Team work at its best – TAPL and its two domains occasionally with two additional transmembrane helices (Oldham et  al., 2007; Gerber et  al., 2008). The TMD of type 2 importers like the vitamin B12 transporter BtuCD from E. coli comprises in total 20 transmembrane helices (Locher et al., 2002). Type 3 importers, also called energycoupling factor (ECF) transporters, are comprised of two cytosolic NBDs, a membrane embedded substrate binding domain (S component) and a transmembrane energycoupling protein, which connects the motor domains with the S component. In group II of ECF transporters, various S components share one energy-coupling module (Zhang, 2013). The TMD of ABC exporters contains 2 × 6 transmembrane helices. In comparison to importers, the NBDs of exporters are more distant from the phospholipid bilayer because the transmembrane helices extend far in the cytosol (Dawson and Locher, 2006). In general, ABC exports appear as full transporters, encoding all domains on a single polypeptide, or half transporters composed of a TMD and a NBD. To constitute an active transport complex, half transporters form homo- or heterodimers (Jones and George, 2004). In human, 48 genes coding for ABC proteins are grouped in seven classes (ABCA – ABCG) (Dean and Annilo, 2005). The four members of the ABCE and ABCF family are soluble proteins whereas the rest constitute half and full transporters. The transporter associated with antigen processing (TAPL, ABCB9) together with TAP1 (ABCB2) and TAP2 (ABCB3) form the TAP family (Zhao et al., 2006). The half transporter TAPL comprises a homodimeric lysosomal peptide transport complex (Zhang et  al., 2000; Leveson-Gower et al., 2004; Wolters et al., 2005), whereas TAP is a heterodimeric endoplasmic reticulum resident peptide transporter composed of TAP1 and TAP2 (Powis et  al., 1991). While the function of the TAP complex in antigen processing is well documented, the physiological role of TAPL is still elusive. The close relationship between TAPL and TAP1/2 is also attested in an almost identical exon organization of the three genes (Uinuk-ool et  al., 2003). Phylogenetic analysis suggests that TAPL is the common ancestor of the TAP family. Its evolving rate is four to ten times slower than for TAP1 and TAP2 genes, which is reflected in a high amino acid sequence identity of 99% between mouse and rat and of 95% between rodent and human (Kobayashi et al., 2000). In human and rat, several splice variants mainly concerning the C-terminal end of TAPL are reported (Kobayashi et al., 2003; Yamaguchi et al., 2004). In contrast to TAP – present only in higher, jawed vertebrates – TAPL orthologs are also found in the agnathic vertebrate sea lamprey and, even in invertebrates like Caenorhabditis elegans as well as in plants (Uinuk-ool et  al., 2003; Kawai et  al., 2009;

Ramos et al., 2011). All of these classes miss the adaptive immune system found in higher vertebrates. Therefore, a more general function of TAPL can be assumed throughout multi-cellular organisms.

Peptide transport The first evidence for peptide transport by TAPL was given by ATP dependent peptide translocation in crude membranes from Sf9 insect cells heterologously expressing TAPL (Wolters et al., 2005). This finding was confirmed by specific peptide transport in isolated lysosomes from TAPL transduced Raji cells, a B lymphoma cell line (Demirel et  al., 2007). Following these investigations, peptide specificity and transport kinetics of TAPL were analyzed in crude membranes as well as in the reconstituted system (Wolters et al., 2005; Zhao et al., 2008). By usage of randomized peptide libraries, the peptide length specificity of TAPL showed a broad range from 6- up to 59-mer peptides, the maximal tested length for a peptide so far, with an optimum of 23-mer peptides. Concerning peptide recognition, side chains as well as peptide backbone including the terminal amino and carboxy groups are involved in the interaction with the transporter (Wolters et al., 2005). The effect of side chain interactions on peptide specificity was furthermore investigated in an isolated reconstituted system diminishing the background from crude membranes. Those studies revealed a side chain specificity that is independent of peptide length and restricted to the N- and C- terminal residue with a preference for positively charged and large hydrophobic residues. In contrast, negatively charged residues or residues like methionine and asparagine at the termini were disfavored. This result opens the way for speculation that the negatively charged membrane leads to an enrichment of peptides in spatial proximity of the transporter supported by the observation that a certain amount of negatively charged phospholipids increases the transport rate of TAPL (Zhao et al., 2008). In brief, TAPL recognizes potential substrates by their N- and C- terminal residues, but with high promiscuity in respect of the sequence and length in between. Regarding transport kinetics, TAPL translocates peptides with low affinity. In crude membranes as well as in the reconstituted system, transport follows MichaelisMenten kinetics (KM(pep)∼10 μm) (Wolters et al., 2005; Zhao et  al., 2008). Moreover, TAPL is a primary active transporter, which strictly requires ATP hydrolysis, proven by impaired transport in the presence of non-hydrolyzable ATP analogs such as AMP-PNP or ATPγS. In respect of

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T. Zollmann et al.: Team work at its best – TAPL and its two domains      969

ATP hydrolysis, transport by reconstituted TAPL follows Michaelis-Menten kinetics, with a Michaelis-Menten constant (KM(ATP)∼98 μm) (Zhao et al., 2008). A KM(ATP) value in this range ensures full activity of TAPL under physiological ATP concentrations. This result is in good agreement with binding of ATP to TAPL analyzed by 8-azido-[α-32P]ATP competitive photocrosslinking assays resulting in a dissociation constant (KD(ATP) ∼100 μm) (Wolters et  al., 2005). Recently, peptide transport of single TAPL complexes in individual liposomes was investigated by dualcolor fluorescence-burst analysis (DCFBA). DCFBA relies on the coincidence of fluorescence bursts in the confocal volume of a microscope, which originate from spectrally well-separated fluorophores that report the number of TAPL molecules per vesicle and the number of peptides translocated. By this method, a turnover rate of 8 peptides per min per TAPL complex was revealed comparable to other ABC transporters (Eytan et  al., 1996; Ambudkar et  al., 1997; Patzlaff et  al., 2003; Wolters et  al., 2005). Moreover, TAPL is an active transporter accumulating peptides against a large concentration gradient. Interestingly, maximal filling stops at a lumenal peptide concentration of 1 mm caused by trans-inhibition in which the transporter is arrested most probably in the outward conformation (Zollmann et al., 2015). A comparison between the two peptide transporters TAPL and TAP shows a good agreement regarding the side chain specificity (Uebel et  al., 1997; Zhao et  al., 2008). However, TAP is a high affinity transporter with a rather narrow peptide length specificity from 8- to 12-mer peptides optimized for peptide loading of major histocompatibility complex (MHC) class I molecules (van Endert et al., 1994; Koopmann et al., 1996; Uebel et al., 1997; Neumann and Tampé, 1999; Eggensperger et al., 2014). TAPL, in contrast, is a high efficient low affinity transporter, which is very promiscuous in peptide sequence and length.

Architecture of TAPL As pointed out, ABC exporters are composed of two cytosolic NBDs and two TMDs with a core of 2 × 6 transmembrane helices (Figure 1). However, several ABC transporters of the ABCB and ABCC subfamily contain an additional N-terminal transmembrane domain (TMD0) (BiemansOldehinkel et  al., 2006). The accessory TMD0s show low sequence homology and vary in length and function, such as intracellular trafficking, protein interaction, activity regulation and post-translational processing (Chan et al., 2003; Koch et  al., 2004; Bandler et  al., 2008). Based on

Figure 1: Model of TAPL. TAPL forms a homodimeric transport complex and each monomer (dark and light green) comprises 10 putative transmembrane helices. The 2 × 6 C-terminal transmembrane helices and both NBDs form the core complex, modeled on the X-ray structure of Sav1866 (PDB ID: 2ONJ). CoreTAPL is fully active in peptide transport but mistargeted to the plasma membrane. The four N-terminal transmembrane helices form the accessory domain TMD0, schematically depicted by four predicted helices. TMD0 acts as a bifunctional platform mediating lysosomal targeting and the interaction with LAMP-1/2.

topology prediction, TMD0 of TAPL forms a four-helix bundle with the N-terminus located in the cytosol. As shown by truncations, the TMD0 of TAPL is not essential for dimerization of the half transporter and peptide transport into lysosomal lumen, as coreTAPL missing TMD0 is fully functional in respect of peptide transport (Kamakura et al., 2008; Demirel et al., 2010). However, as demonstrated by quantitative immuno-fluorescence microscopy as well as by subcellular fractionation, coreTAPL is not localized in lysosomal membranes but is targeted to the plasma membrane (Demirel et al., 2010). TMD0 like wt TAPL is targeted to lysosomes. Furthermore, by co-expression of both parts TMD0 is able to target coreTAPL to lysosomes by non-covalent interaction (Demirel et al., 2010). One TMD0 is sufficient to direct the TAPL complex to lysosomes as derived from co-expression of coreTAPL and wt TAPL (Ö. Demirel and R.A., unpublished results). The lysosomal targeting sequence as well as the intracellular route of TAPL is not yet discovered. As wt TAPL is not surface biotinylated, a direct pathway from the Golgi to lysosomes can be assumed. In conclusion, the TMD0 is essential for lysosomal localization of the polypeptide transporter TAPL. By tandem affinity purification coupled with mass spectrometry the lysosomal-associated membrane proteins LAMP-1 and LAMP-2 were identified as interaction partners of wt TAPL but not of coreTAPL. The interaction is mediated by TMD0 of TAPL (Demirel et al., 2012).

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970      T. Zollmann et al.: Team work at its best – TAPL and its two domains LAMP-1/2 are type-1 N- and O-glycosylated membrane proteins involved in several cellular functions (Eskelinen et  al., 2003). LAMP-1 is not an essential gene as its deficiency shows only mild regional activation of astroglia and altered immuno-reactivity of cathepsin D. Moreover, LAMP-1 deficiency goes along with elevated LAMP-2 expression (Andrejewski et al., 1999). In contrast, LAMP-2 deficiency causes a severe phenotype in mice with a death rate of 50% in the first 20–40  days after birth (Tanaka et al., 2000). In LAMP-2 knock-out cells an accumulation of autophagic vacuoles and impaired chaperone mediated autophagy (CMA) is obeserved (Cuervo and Dice, 1996). Importantly, TAPL interacts with the splice variant LAMP-2B but not with the CMA receptor LAMP-2A. The interaction of TAPL with LAMP-1/2 has no impact on subcellular trafficking nor on the transport activity of TAPL. However, it strongly stabilizes the transporter against proteolytic degradation reflected in a significant decreased half-life in LAMP knock-out cells. Interestingly, coreTAPL, not interacting with LAMP-1/2, shows a short half-life even in the presence of LAMP-1/2 (Demirel et  al., 2012). Membrane proteins released from the trans-Golgi network are

labeled by ubiquitin for degradation and are directed to multivesicular bodies (MVBs) where the proteins are internalized in intraluminal vesicles (ILVs) by the ESCRT complex (endosomal sorting complex required for transport) (Tanno and Komada, 2013). Subsequently, the MVBs fuse with lysosomes and the ILVs are degraded by lysosomal hydrolases (Henne et  al., 2011). LAMP-1 and LAMP-2 shuttle between lysosomes, late endosomes and the limiting membrane of MVBs, but are hardly detected in ILVs (Escola et al., 1998; Denzer et al., 2000). It can be speculated that TAPL is excluded from ILVs because of the interaction with LAMP, whereas coreTAPL is not retained in the limiting membrane and, therefore, enters more frequently the endo-lysosomal pathway for degradation (Figure 2).

Expression of TAPL The tissue distribution of TAPL was analyzed by comparing mRNA levels in tissues of adult rat, mice and human. TAPL was identified as a nearly ubiquitous expressed

Figure 2: Model of TAPL stabilization by the interaction with LAMP-1/2. Wt TAPL is targeted to lysosomes most likely by the direct pathway, where it transports peptides from the cytosol into the lysosomal lumen. By interaction with LAMP-1/2, TAPL is retained in the limiting membrane of MVB and, thus, is prevented from internalization into ILVs destined for lysosomal degradation. CoreTAPL does not contain the lysosomal targeting signal and is delivered to the plasma membrane (dashed arrows). After internalization from the plasma membrane probably induced by ubiquitination, coreTAPL is not retained in the limiting membrane of MVBs by the interaction with LAMP-1/2. Therefore, it is internalized in ILVs, which are, subsequently, degraded in lysosomes.

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T. Zollmann et al.: Team work at its best – TAPL and its two domains      971

protein. For all three species, elevated mRNA levels were detected in the central nervous system and testis (Yamaguchi et  al., 1999; Zhang et  al., 2000; Nishimura and Naito, 2005). Also in sea lamprey, an agnathic vertebrate, TAPL distribution coincides with the described results of mammals (Uinuk-ool et al., 2003). Immunohistochemistry staining of rat and mouse testes indicated TAPL expression in Sertoli cells (Zhang et al., 2000). These specialized cells are part of the seminiferous tubules and perform a number of functions relevant for spermatogenesis, such as providing nutrition and structural support but also phagocytosis of residual bodies and degenerated cells. A strong increase in TAPL expression was also detected during maturation of monocytes to professional antigen presenting cells, like dendritic cells and macrophages (Demirel et al., 2007).

Physiological role of TAPL In line with the broad tissue distribution of TAPL is the promoter region of the ABCB9 gene, which includes a GC-rich region with multiple GC-boxes serving as possible binding sites for the ubiquitous transcription factor Sp1 (­Kobayashi et  al., 2003; Uinuk-ool et  al., 2003). Sp1 is involved in a variety of cellular processes such as cell growth, apoptosis, differentiation and immune response (Li et al., 2004). Together with the presence of TAPL orthologs in phylogenetic distant species, TAPL seems to take over a more general function as a housekeeping factor preventing peptide accumulation in the cytosol and, therefore, possible toxic or stressful effects for the cells. The most clear-cut indications for TAPL function are from studies on the TAPL orthologs HAF-4 and HAF-9 from the nematode C. elegans, which both show a sequence identity of 38% to TAPL (Kawai et al., 2009). Localization of both proteins was shown in nonacidic, LMP-1 containing, intestinal granules defined as ‘late lysosomes’. Further investigations indicated that HAF-4 and HAF-9 form heterodimers (Tanji et al., 2013), but in contrast to its mammalian ortholog this complex does neither interact with the LAMP-1 homologue LMP-1 nor is its stability dependent on LMP-1. Knock-out of HAF-4 or HAF-9 resulted in a loss of this specific subtype of granules. Interestingly, the activity of HAF-4 is essential for granule formation as a HAF-4 mutant inactive in ATP hydrolysis could not restore nonacidic granules. The phenotype of HAF-4 or HAF-9 deficient nematodes showed no effect on the body form, the size or the movement of the nematode. However, defects of brood size, growth rate and defecation rate were

observed (Kawai et al., 2009). Taken together these results hint at a role of these ABC transporters in the biogenesis of nonacidic intestinal granules. Whether a TAPL knockout in mammals would have related effects on lysosomes and would result in a similar phenotype remains to be investigated. Apart from its ubiquitous function in polypeptide clearance or even in the biogenesis of lysosomes, a role in the immune response might also be possible. TAPL expression is strongly induced during the maturation of monocytes to professional antigen presenting dendritic cells and macrophages (Demirel et  al., 2007). Further, it could be ruled out that TAPL can substitute for TAP1/2 in respect of the classical MHC class I antigen presentation pathway. The increase of TAPL expression during differentiation of dendritic cells suggests that it is involved in a non-classical pathway like the presentation of exogenous antigens on MHC I molecules, also called cross-presentation, or the presentation of endogenous, cytosolic antigens on MHC II molecules. For cross-presentation on MHC class I complexes, two separate pathways exist in dendritic cells. In the vacuolar pathway exogenous antigens are endocytosed and degraded in phagosomes, where the loading on MHC class I molecules also takes place. Peptide bound MHC class I is then trafficked to the plasma membrane. The so-called cytosolic pathway is defined by proteasomal processing of endocytosed antigens, which have to be, prior to that, exported from phagosomes into the cytosol. After degradation, the processed peptides are translocated by TAP1/2 either into the ER or into endosomes or phagosomes, where peptide loading onto MHC I is carried out (Schuette and Burgdorf, 2014). However, the cytosolic, proteasomaldependent pathway can also take place in a TAP1/2-independent manner (Merzougui et al., 2011). It is possible that TAPL is part of this TAP-independent pathway and, therefore, involved in the activation of CD8+ cytotoxic T-cells. The localization of TAPL in dendritic cells is not investigated and, thus, a phagosomal or lysosomal localization can be imagined (Figure 3A). Although MHC class II presents antigenic peptides of endocytosed antigens to CD4+ T-helper cells, a large portion of MHC class II presented peptides are derived from endogenous proteins (Rudensky et al., 1991; Chicz et  al., 1993; Dongre et  al., 2001). This is an important pathway to present viral antigens of infected dendritic cells on MHC class II. Moreover, this is an essential step for negative selection during T-cell development. Autophagy is one route to acquire cytosolic proteins in the lysosomal lumen or MHC class II loading compartment (Virgin and Levine, 2009; Mizushima and Levine,

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972      T. Zollmann et al.: Team work at its best – TAPL and its two domains

Figure 3: Putative functions of TAPL in antigen presentation. (A) Cross-presentation of exogenous antigens on MHC class I molecules. After internalization of exogenous antigens in dendritic cells or macrophages, the antigens are transported into the cytosol by an unknown mechanism. In the cytosol, the antigens are degraded by the proteasome and processed peptides are translocated into phagosomes or lysosomes for binding onto newly synthesized or recycled MHC class I molecules, respectively. Subsequently, loaded MHC class I molecules are transferred to the cell surface to present their cargo to CD8+ cytotoxic T-cells. The shuttling of cytosolic peptides into phagosomes is a TAP dependent pathway. However, in TAP deficient antigen presenting cells, cross-presentation by a proteasomal dependent route is still active, implying TAPL as an additional factor in cross-presentation (Merzougui et al., 2011). (B) Presentation of endogenous peptides on MHC class II molecules. To present peptides derived from cytosolic pathogens to activate CD4+ T-cells or self-peptides for negative selection during T-cell maturation, cytosolic proteins are degraded by the proteasome and processed peptides are shuttled into lysosomes for loading onto MHC class II molecules. Subsequently, peptide bound MHC class II are exposed on the cell surface of professional antigen presenting cells to CD4+ helper T-cells. It was shown that peptides derived from microinjected ovalbumin are presented on the cell surface by MCH class II molecules in a proteasome dependent but TAP as well as autophagy independent manner, therefore suggesting TAPL as transporter responsible for this pathway (Dani et al., 2004).

2010). However, a pathway was reported in which peptides microinjected into the cytosol were loaded onto MHC class II in a LAMP-1 positive cellular compartment in a proteasome dependent but TAP and autophagy independent manner (Dani et al., 2004). In addition, a proteasome dependent but TAP and LAMP-2 independent loading of endogenous antigens on MHC class II in vaccinia virus infected murine dendritic cells was recently demonstrated (Thiele et  al., 2015). Therefore, it can be speculated that TAPL is the transporter responsible for this pathway, which takes place in professional antigen presenting cells (Figure 3B). Acknowledgments: This work was supported by the ­German Research Foundation via SFB807 – Transport and Communication across Membranes (R.A.) and Fond der Chemischen Industrie (T.Z. and R.A.)

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