br Possible complementarity of trimming pathways Determining
Possible complementarity of trimming pathways Determining the exact pathway for the generation or destruction of MHCI peptide ligands by ERAP1 is important for our understanding of the shaping of the immunopeptidome and for designing inhibitors that can manipulate it. It is also possible however that both pathways operate in parallel depending on the peptide and its MHC-binding kinetics and affinity. Slow-binding or weaker binding peptides may spend more time in solution to be trimmed or destroyed by ERAP1, whereas some peptides may associate with MHCI immediately after they are translocated in the ER and can only be trimmed in that context. This notion adds an additional level of complexity in the generation of the immunopeptidome. The effects of ERAP1 NCT-502 on the immunopeptidome are however complex (Nagarajan et al., 2016; Barnea et al., 2017; Martin-Esteban et al., 2017) suggesting that our current understanding of the underlying mechanisms may not yet be sufficient to fully explain the physiological process.
On-MHC trimming by ERAP2 and IRAP? The other oxytocinase subfamily members ERAP2 and IRAP also have been proposed to play important roles in antigen processing in specific different cellular contexts (Tsujimoto and Hattori, 2005). ERAP2 has been proposed to act as an accessory aminopeptidase and supplement ERAP1 specificity while IRAP to operate in a separate pathway of cross-presentation (Saveanu et al., 2005; Saveanu et al., 2009). Interestingly ERAP2 and IRAP do not share the same enzymatic properties with ERAP1 regarding length preference and rather prefer to trim peptides of intermediate length (Mpakali et al., 2015a; Stamogiannos et al., 2015; Mpakali et al., 2015b). Although ERAP2 was proposed to trim on-MHC bound peptide precursors in the context of an ERAP1/ERAP2 dimer, neither ERAP2 nor IRAP alone is known if they can perform the same function. Still, multiple conformations have been suggested to be accessible for these two enzymes also, opening up the possibility that they also employ similar mechanisms to peptide trimming as ERAP1 (Mpakali et al., 2015a; Birtley et al., 2012; Mpakali et al., 2015b; Papakyriakou and Stratikos, 2017).
Future directions—insights It has been 15 years since the first description of the role of ERAP1 in antigenic peptide generation (Serwold et al., 2002; York et al., 2002; Saric et al., 2002) and although many studies have demonstrated a key role in immune homeostasis and in immune dysfunction, significant controversy remains regarding its molecular mechanism and physiological substrate. The two pathways described in this review can serve as a distillation of current literature and as a starting point to design experiments to discern the relative importance and contributions of each proposed pathway in vivo. Given the importance of ERAP1 in shaping immune responses, a deeper understanding of the relative importance of solution versus on-MHC processing is necessary to allow both prediction of the repercussions of ERAP1 activity modulation on immune function and also the optimization of small molecule inhibitors of ERAP1 for pharmacological applications.
Introduction Aminopeptidase N (APN, CD13) is a zinc-dependent membrane bound exopeptidase, consisting of 967 amino acids with a short cytoplasmic part, a single transmembrane domain and a large extracellular catalytic domain. The enzyme preferentially hydrolyzes basic or neutral amino acid residues from the unsubstituted N-terminals of oligopeptides, such as enkephalins, angiotensins, P-substance, cytokines and others. As a widely distributed and over-expressed enzyme in malignant cells, it is associated with the growth, invasion and metastasis of diverse cancers.3, 4, 5, 6, 7 Moreover, documents suggested that APN expression, specially on the endothelium of angiogenic vasculature, could be activated by angiogenic signals and is essential for capillary tube formation.8, 9 All these findings make APN a promising antitumor target.