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  • N terminally extended antigenic peptide precursors that surv

    2024-05-17

    N-terminally extended antigenic peptide precursors that survive cytosolic degradation and enter the ER, need to be further processed by ERAP1 and/or ERAP2, in order to acquire the right length required for MHCI binding. ERAP1 (ERAAP in mouse) is an IFN-γ-inducible, metalloaminopeptidase that trims N-terminal residues of extended peptide precursors down to 8–9 faah inhibitors (Chang et al., 2005; Serwold et al., 2002; York et al., 2002). ERAP1 can also limit the production of antigenic peptides by overtrimming them (York et al., 2002; Saric et al., 2002). Several independent studies using RNA interference or knock-out animals confirmed this key involvement of ERAP1 in antigen presentation (Chang et al., 2005; Serwold et al., 2002; York et al., 2002; Saric et al., 2002). In addition these studies demonstrated that the absence of ERAP1 activity can lead to reduced number of peptide-MHCI complexes on the cell surface that also have a shorter half-life (Hammer et al., 2007; Yan et al., 2006). In ERAP1-deficient mice the reduction in MHCI expression was proven to be due to faster dissociation of peptide-MHCI complex from the cell surface rather than to a slower rate of complex assembly in the ER (Hammer et al., 2006). Furthermore, ERAP1 plays roles in vivo in immune responses to viruses, either enhancing or reducing CTL responses to particular viral epitopes and thereby helping establish immunodominance hierarchy (York et al., 2006). ERAP1 has also been shown to regulate tumor immunogenicity and cytotoxic response to cancer cells (James et al., 2013; Keller et al., 2015; Cifaldi et al., 2011) and to play a role in regulating innate and inflammatory immune responses (Aldhamen et al., 2015; Goto et al., 2014; Cui et al., 2003).
    Effects of ERAP1 on the immunopeptidome The collection of peptides that are presented by MHCI molecules on the cell surface define the immunopeptidome (Admon and Bassani-Sternberg, 2011). Although MHCI allelic variation is the most important determinant of the composition of the immunopeptidome, ERAP1 is an additional key editor that affects immunopeptidome quality and constitution (Georgiadou and Stratikos, 2009; Alvarez-Navarro and Lopez de Castro, 2014). As noted above, reduction or loss of ERAP1 expression in cell lines or mouse models, led to presentation of unstable and structurally unique peptide-MHCI complexes to the cell surface. Many conventional complexes were lost, while concomitantly, new, highly immunogenic complexes emerged (Hammer et al., 2007). In other words, in the absence of ERAP1 trimming activity, some endogenous antigens were poorly presented, while presentation of other antigens was enhanced or remained unaffected, suggesting a selective effect on the repertoire of peptide-MHCI complexes (Hammer et al., 2006; York et al., 2006; Nagarajan et al., 2016; Barnea et al., 2017). Additionally, a large fraction of the novel epitopes that arose, were longer in length and carried extended N-termini (Blanchard et al., 2010). Taken together, it appears that ER proteolysis defines the composition and the structure of peptides presented to CD8+ cells.
    Dimerization and synergism with ERAP2 Although ERAP1 is considered to be the dominant aminopeptidase in the ER for trimming peptide precursors, recent work has highlighted a second trimming enzyme, ERAP2, to be important for correct antigen processing. ERAP2 is highly homologous to ERAP1 (50% sequence identity) and can efficiently generate antigenic peptides in vitro (Saveanu et al., 2005; Mpakali et al., 2015a). ERAP2 however, shows distinct trimming patterns compared to ERAP1, has a different specificity for N-terminal residues and appears to select peptides of different lengths (Mpakali et al., 2015a; Zervoudi et al., 2011). It has been proposed that ERAP2 activity is complementary to ERAP1 and several antigenic epitopes with complex or longer extensions seem to require both ERAP1 and ERAP2 for correct processing (Saveanu et al., 2005; Lorente et al., 2013). ERAP1 and ERAP2 co-localize inside the cell, co-elute in chromatographic microsome fractionation and co-immunoprecipitate (Saveanu et al., 2005). This has led to the suggestion that the human ER has a non-redundant system of physically associated ERAP1 and ERAP2 heterodimer that ensures highly efficient trimming of diverse precursor epitopes with complex N terminal extensions. A direct association of ERAP1 and ERAP2 has not however been demonstrated yet by biophysical methods. Recently, researchers used a leucine-zipper hetero-dimerization domain to construct an ERAP1/ERAP2 heterodimer and demonstrated that dimerization affected their enzymatic properties, suggesting that an ERAP1/ERAP2 dimer may be the biologically relevant antigen trimming entity in humans (Evnouchidou et al., 2014). Structural analysis of ERAP2 by x-ray crystallography indicated a putative homo-dimerization domain in ERAP2 that utilizes residues that are largely conserved in ERAP1 (Birtley et al., 2012). Furthermore, both ERAP1 and ERAP2 are retained in the ER although they do not possess any ER retention signals, suggesting that they are retained there though protein-protein interactions that exist only inside the ER (Hattori and Tsujimoto, 2013). Indeed, disulfide bond formation between exon 10 of ERAP1 and ERp44, a factor involved in disulfide bond formation in the ER, has been suggested to be the main mechanism for ERAP1 retention in the ER and to regulate its release and thus the extracellular degradation of angiotensin II, although other protein-protein interactions with ER chaperones or the Peptide Loading Complex may also be important (Hattori et al., 2012;Hisatsune et al., 2015; Blees et al., 2017). ERAP2 contains an exon of similar length, which has little homology with the ERAP1 exon 10 but still retains the ERp44 interacting cysteine and has been found to fold in an appendix-like structure containing an internal disulfide bond and a helical segment (Mpakali et al., 2015a). It is currently not known if this exon is responsible for ERAP2 retention in the ER, although in an ERAP2 crystal structure it was found to make interactions with an adjacent ERAP2 molecule in the crystal, suggesting that it may constitute a protein-protein interaction structural motif (Mpakali et al., 2015a). IRAP, on the contrary, does not contain a similar exon, but has a transmembrane and a cytosolic domain that target it to endosomal vesicles or the cell membrane and have been suggested to be important for interactions and signaling (Saveanu and van Endert, 2012; Chai et al., 2004; Keller, 2003).