{"gene":"ERAP2","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":2005,"finding":"ERAP1 and ERAP2 form heterodimeric complexes in the endoplasmic reticulum and have complementary, concerted aminopeptidase activities: ERAP1 cannot remove certain N-terminal amino acids that ERAP2 trims efficiently, and trimming of longer peptide precursors requires the concerted action of both enzymes both in vitro and in vivo for MHC class I antigen presentation.","method":"Co-immunoprecipitation (physical association), in vitro peptide digestion assays, cellular antigen presentation assays, in vivo co-localization","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro reconstitution + in vivo functional assay + physical interaction, replicated across multiple experimental approaches in a highly cited foundational paper","pmids":["15908954"],"is_preprint":false},{"year":2010,"finding":"ERAP2 Haplotype B undergoes differential splicing, encoding a truncated protein that is degraded by nonsense-mediated decay (NMD), resulting in ERAP2 deficiency. Haplotype B homozygotes have lower surface MHC class I expression on B cells, demonstrating that naturally occurring ERAP2 deficiency functionally affects MHC class I antigen presentation.","method":"Genetic analysis of haplotypes, RT-PCR for splice forms, flow cytometry for surface MHC class I expression in primary lymphocytes with defined ERAP2 genotypes","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (genetics, splicing, functional cell surface assay), strong evidence from population-level and cellular experiments","pmids":["20976248"],"is_preprint":false},{"year":2014,"finding":"ERAP1-ERAP2 dimerization increases peptide-trimming efficiency: stabilized ERAP1-ERAP2 heterodimers produce mature MHC class I epitopes more efficiently than a mix of the two enzymes unable to dimerize. Physical interaction with ERAP2 changes basic enzymatic parameters of ERAP1 and improves its substrate-binding affinity through allosteric effects.","method":"Production of stabilized ERAP1-ERAP2 heterodimers, enzymatic assays comparing heterodimers vs. enzyme mixtures unable to dimerize, kinetic parameter measurements","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro reconstitution with stabilized heterodimers and kinetic analysis; functionally rigorous","pmids":["24928998"],"is_preprint":false},{"year":2016,"finding":"ERAP1/ERAP2 heterodimers can trim MHC class I-bound precursor peptides to their correct and final lengths (albeit more slowly than free precursors), and trimming of MHC I-bound precursors by ERAP1/2 increases the conformational stability of MHC I/peptide complexes, supporting a peptide editing model.","method":"In vitro trimming assays using ERAP1/2 heterodimers with free and HLA-B*0801-bound N-terminally extended model and natural peptides; conformational stability measurements","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with defined substrates (free and MHC-bound), multiple functional readouts","pmids":["27514473"],"is_preprint":false},{"year":2013,"finding":"ERAP1 and ERAP2 act concertedly in trimming viral HLA-B27-restricted peptide precursors: each enzyme can use the degradation products of the other as substrates for new N-terminal trimming, with double enzyme digestions producing increased amounts of natural HLA-B27 ligands compared to single enzyme digestions.","method":"In vitro peptide digestion with ERAP1 and/or ERAP2, mass spectrometry identification of products","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro assay with mass spectrometry, single lab, moderate evidence for concerted activity","pmids":["24223975"],"is_preprint":false},{"year":2017,"finding":"ERAP1 and ERAP2 have significant but distinct and largely separate effects on the HLA-B*27 peptidome in human cells: ERAP1 effects relate primarily to peptide length and N-terminal Ala1 frequency, while ERAP2 effects additionally reduce peptides with N-terminal basic residues and lower the affinity of the peptidome. Both enzymes largely act as separate entities in vivo.","method":"Quantitative label-free mass spectrometry comparison of HLA-B*27:05 peptidomes from cells with various ERAP1/ERAP2 phenotypes","journal":"Journal of autoimmunity","confidence":"High","confidence_rationale":"Tier 2 — quantitative peptidomics in multiple cell contexts with defined ERAP phenotypes, multiple orthogonal comparisons","pmids":["28063628"],"is_preprint":false},{"year":2018,"finding":"ERAP2 alters the HLA-A*29:02 peptidome in a manner distinct from HLA-B*27: presence of ERAP2 increases amounts of peptides >9-mers and alters N-terminal residues toward less ERAP2-susceptible, more hydrophobic residues. Unproductive binding to ERAP2 may protect some peptides from ERAP1 over-trimming.","method":"Lentiviral transduction of ERAP2 into ERAP2-negative cell lines, label-free quantitative mass spectrometry of A*29:02 peptidomes","journal":"Molecular & cellular proteomics","confidence":"High","confidence_rationale":"Tier 2 — quantitative peptidomics with controlled ERAP2 expression, replicated in two independent cell line comparisons","pmids":["29769354"],"is_preprint":false},{"year":2019,"finding":"ERAP2 depleted by CRISPR/Cas9 knockout shows functional redundancy with ERAP1 in processing HLA-B*51:01 ligands: in the absence of ERAP1, ERAP2 alone can perform similar and significant processing of B*51:01 ligands. ERAP1 and ERAP2 have distinct but complementary and partially redundant effects on the B*51:01 peptidome, required for its optimization and maximal surface expression.","method":"CRISPR/Cas9 knockout of ERAP1, ERAP2, or both; label-free quantitative mass spectrometry of HLA-B*51:01 peptidomes; surface HLA expression measurement","journal":"Molecular & cellular proteomics","confidence":"High","confidence_rationale":"Tier 2 — CRISPR KO with quantitative peptidomics in multiple KO combinations, strong mechanistic conclusions","pmids":["31092671"],"is_preprint":false},{"year":2020,"finding":"ERAP2 shapes the natural HLA-B*27:05 ligandome in live cells: in absence of ERAP2, peptides with N-terminal basic residues and minority canonical P2 residues are enriched, and alterations in residue frequencies at P3, P7, and PΩ positions are observed. Additionally, ERAP2-dependent cellular peptides show high similarity to sequences from arthritogenic bacteria including Campylobacter jejuni.","method":"CRISPR/Cas9 editing of ERAP2 in HLA-B*27:05-expressing cells, quantitative tandem mass spectrometry of natural ligandome, bioinformatics sequence alignment","journal":"Molecular & cellular proteomics","confidence":"High","confidence_rationale":"Tier 2 — CRISPR KO with quantitative peptidomics, rigorous controls","pmids":["32265295"],"is_preprint":false},{"year":2019,"finding":"ERAP2 has substantial influence on the HLA-B*40:02 peptidome: depletion of ERAP2 by CRISPR KO causes major effects on N-terminal residue frequencies (increased basic and small residues, decreased aliphatic/aromatic ones) and quantitative changes in peptide amounts, with ERAP2 affecting the generation/destruction balance of HLA-B*40:02 ligands.","method":"CRISPR/Cas9 knockout of ERAP2 in C1R-B*40:02, label-free quantitative mass spectrometry peptidome comparison","journal":"Molecular & cellular proteomics","confidence":"High","confidence_rationale":"Tier 2 — CRISPR KO with quantitative peptidomics","pmids":["31530632"],"is_preprint":false},{"year":2022,"finding":"ERAP2 preferentially trims peptides shorter than 9 residues, while ERAP1 efficiently trims peptides longer than 9 residues. The optimal ligands for either enzyme act as inhibitors of the other: octamers reduce long-peptide trimming by ERAP1, while peptides longer than nonamers inhibit ERAP2 activity. This mutual inhibition constitutes a synergistic self-modulation mechanism shaping the MHC-I peptidome.","method":"Biochemical enzymatic assays and proteomic studies with defined peptide substrates, biological verification","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 1-2 — biochemical enzymatic assays with defined substrates, single lab","pmids":["36569828"],"is_preprint":false},{"year":2021,"finding":"ERAP2 increases the abundance of a specific peptide submotif in the HLA-A29 immunopeptidome that is highly selective for HLA-A29. ERAP2 also imprints internal sequence specificity in the immunopeptidome. The effects of ERAP2 on N-terminal residues of HLA-A29 ligands are shared across HLA allotypes, but the A29-specific motif is uniquely generated in the presence of ERAP2.","method":"HLA-A29-based and pan-class I immunopurification, isotope-labeled naturally processed peptide sequencing by mass spectrometry in patient-derived antigen-presenting cells with and without ERAP2","journal":"Frontiers in immunology","confidence":"High","confidence_rationale":"Tier 2 — quantitative immunopeptidomics in patient-derived cells, replicated finding","pmids":["33717175"],"is_preprint":false},{"year":2022,"finding":"Crystal structure of ERAP2 bound to a phenylsulfamoyl benzoic acid inhibitor (compound 61) reveals that the inhibitor binds near the catalytic center of ERAP2 at a distinct site from peptidomimetic inhibitors, and inhibits by an uncompetitive mechanism. His904 in ERAP2 is a key selectivity determinant governing compound binding at the allosteric site; mutation of His904 to alanine reveals a cryptic allosteric site permitting activation of ERAP2 by compound 3.","method":"Crystal structure determination of ERAP2-inhibitor complex, enzymatic inhibition assays, site-directed mutagenesis of His904","journal":"ACS chemical biology","confidence":"High","confidence_rationale":"Tier 1 — crystal structure plus mutagenesis and kinetic analysis defining mechanism of inhibition and selectivity determinants","pmids":["35767698"],"is_preprint":false},{"year":2022,"finding":"Co-crystallization of ERAP2 with three different inhibitors discovered by kinetic target-guided synthesis reveals the binding mode of selective ERAP2 inhibitors; selected analogues engage ERAP2 in cells and inhibit antigen presentation in a cellular context.","method":"Kinetic target-guided synthesis, co-crystallization and X-ray structure determination, cellular ERAP2 engagement assays, antigen presentation assays","journal":"Angewandte Chemie","confidence":"High","confidence_rationale":"Tier 1 — crystal structures with multiple inhibitors, cellular functional validation","pmids":["35904863"],"is_preprint":false},{"year":2022,"finding":"A shorter form of ERAP2 is generated in macrophages by autocatalytic cleavage within a distinctive structural motif in an acidic microenvironment, independently of ERAP2 haplotype. This 'short' ERAP2 binds IRAP (insulin-regulated aminopeptidase), and the two molecules are co-expressed in endosomes and on the cell membrane, suggesting a function for ERAP2 outside the ER in the angiotensin system.","method":"Western blot characterization of short ERAP2 form, co-immunoprecipitation of ERAP2 short with IRAP, co-localization by microscopy, subcellular fractionation, autocatalytic cleavage assays","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2-3 — biochemical characterization plus co-IP and co-localization, single lab","pmids":["35563348"],"is_preprint":false},{"year":2019,"finding":"ERAP2 is secreted from activated human monocyte-derived macrophages (MDMs) in response to IFNγ/LPS stimulation. Exogenous recombinant ERAP2-FL reduces HIV-1 viral replication in PBMCs, associated with increased IFNγ and CD69 mRNA expression and increased perforin-expressing CD8+ T cells.","method":"Mass spectrometry identification of ERAP2 in secretome of activated MDMs; addition of recombinant ERAP2 to PBMC cultures with p24 viral antigen quantification; flow cytometry and gene expression analysis","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2-3 — MS identification of secreted protein plus functional assay, single lab","pmids":["31379846"],"is_preprint":false},{"year":2013,"finding":"EpCAM associates with ERAP2 in breast cancer cells: ERAP2 co-precipitates with EpCAM and co-localizes in the cytoplasm/ER and plasma membrane, suggesting a novel interaction that may regulate EpCAM processing and antigen presentation in cancer.","method":"Co-immunoprecipitation followed by mass spectrometry, co-localization by microscopy, in vitro expression in dog pancreas rough microsomes","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 — single Co-IP/MS finding with partial follow-up, no functional mechanism established","pmids":["23988446"],"is_preprint":false},{"year":2021,"finding":"ERAP2 plays a role in autophagy and activation of pancreatic stellate cells (PSCs) via the unfolded protein response (UPR) signaling pathway: ERAP2 knockdown by siRNA inhibited UPR-mediated autophagy and led to inactivation of PSCs, attenuating tumor-stromal interactions by inhibiting IL-6 and fibronectin production. In vivo, ERAP2 knockdown suppressed xenografted tumor growth and fibrosis.","method":"siRNA knockdown of ERAP2 in PSCs, autophagy and ER stress assays, gene expression microarray, IL-6 and fibronectin measurement, orthotopic xenograft mouse model","journal":"Pancreatology","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with defined cellular and in vivo phenotypes, but mechanism linking ERAP2 to UPR/autophagy is not fully characterized","pmids":["34642112"],"is_preprint":false},{"year":2022,"finding":"ERAP2 inhibition in MOLT-4 T lymphoblast leukemia cells induces significant shifts in the MHC class I immunopeptidome: more than 20% of detected peptides are either novel or significantly upregulated, with inhibitor-induced peptides being predominantly 9-mers with sequence motifs and predicted affinity consistent with optimal MHC class I ligands.","method":"Selective ERAP2 inhibitor treatment, MHC class I immunopurification, LC-MS/MS peptidomics of MOLT-4 cells","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 — pharmacological inhibition with quantitative peptidomics, single lab","pmids":["35163832"],"is_preprint":false},{"year":2023,"finding":"ERAP2 alone, when expressed in ERAP-deficient cells, elicits strong CTL responses toward the Tyrosinase368-376 tumor epitope; ERAP2 also influences recognition of gp100209-217 and enhances T cell recognition of MART-126/27-35 in the absence of ERAP1 expression. In vitro, ERAP1 and ERAP2 differently customize TAP-dependent N-terminally extended epitope precursor peptides.","method":"Expression of ERAP2 in ERAP-deficient cells, CTL recognition assays, in vitro peptide trimming assays with TAP-dependent precursors","journal":"Molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 — functional cellular assays plus in vitro trimming, single lab","pmids":["36608422"],"is_preprint":false},{"year":2020,"finding":"A new ERAP2 isoform (ERAP2/Iso3) is expressed from the major haplotype following microbial stimulation (influenza, LPS, CMV, HIV, SARS-CoV-2 antigens) in PBMCs and MDMs. Unlike ERAP2-wt, ERAP2/Iso3 is unable to trim peptides for MHC class I loading but retains the ability to dimerize with both ERAP2-wt and ERAP1-wt, contributing to an alternative cellular immune-peptidome.","method":"RT-PCR/Quantigene for isoform mRNA expression, Western blot for protein, dimerization assays, stimulation with multiple pathogens","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2-3 — mRNA and protein confirmed, functional trimming and dimerization assessed, single lab","pmids":["32847031"],"is_preprint":false},{"year":2023,"finding":"ERAP2 expression is directly controlled by the splice region variant rs2248374, demonstrated by reciprocal allelic replacement. Additionally, disease-associated variants in the downstream LNPEP gene promoter independently regulate ERAP2 expression through long-range chromatin contacts between LNPEP and ERAP2 promoters, with stronger interactions in patients carrying autoimmune disease-susceptibility alleles.","method":"Reciprocal allelic replacement (CRISPR), allele-specific conformation capture (3C) assays measuring chromatin contacts, reporter assays","journal":"Cell genomics","confidence":"High","confidence_rationale":"Tier 1-2 — reciprocal allelic replacement plus allele-specific chromatin conformation capture, multiple orthogonal methods establishing cis-regulatory mechanism","pmids":["38190099"],"is_preprint":false},{"year":2016,"finding":"Discovery of potent inhibitors selective for ERAP2 (Ki=100–350 nM) among phosphinic dipeptide analogues; N'-substituted α,β-diaminophosphonates and phosphinates showed selectivity toward ERAP2 only, consistent with the P1 basic substrate-oriented specificity of ERAP2, distinguishing it from ERAP1.","method":"In vitro enzymatic inhibition screening of 50 phosphonic/phosphinic acid compounds against ERAP1 and ERAP2, Ki determination","journal":"Bioorganic & medicinal chemistry letters","confidence":"Medium","confidence_rationale":"Tier 1 — in vitro enzymatic assays with defined inhibitors revealing substrate specificity, single study","pmids":["27390066"],"is_preprint":false},{"year":2022,"finding":"ERAP2 contributes to modulation of neutrophil function when secreted extracellularly: recombinant ERAP2 is internalized by neutrophils and triggers their activation (increased MAC-1+CD66b+, cytokine release), increases migration capacity, autophagy, and phagocytosis activity, and reduces ROS accumulation.","method":"Recombinant human ERAP2 supplementation to neutrophil cultures, Western blot for internalization, flow cytometry for activation markers, transwell migration assay, ROS measurement, autophagy assay","journal":"Frontiers in cell and developmental biology","confidence":"Low","confidence_rationale":"Tier 3 — single lab, functional assays with exogenous protein, no molecular mechanism established","pmids":["39839670"],"is_preprint":false}],"current_model":"ERAP2 is an ER-resident zinc metalloprotease that trims N-terminal residues from peptide precursors (preferring shorter substrates <9-mers and N-terminal basic residues) to generate optimal MHC class I ligands; it physically associates with ERAP1 to form heterodimers that have superior and complementary peptide-trimming efficiency through allosteric modulation of ERAP1 kinetics, while ERAP2 expression is controlled by a splice-region variant (rs2248374) and by long-range chromatin contacts from the LNPEP promoter, and an autocatalytic short form of ERAP2 is secreted by macrophages where it binds IRAP in endosomes, suggesting additional functions in the renin-angiotensin system beyond ER antigen processing."},"narrative":{"teleology":[{"year":2005,"claim":"The foundational question of whether ERAP2 functions independently or cooperatively with ERAP1 was resolved: the two enzymes form ER-resident heterodimers with complementary specificities required for concerted trimming of MHC class I peptide precursors.","evidence":"Co-immunoprecipitation, in vitro peptide digestion, and cellular antigen presentation assays","pmids":["15908954"],"confidence":"High","gaps":["Stoichiometry and structural basis of the heterodimer were unknown","Whether dimerization alters enzymatic kinetics was not addressed","In vivo relevance to specific HLA allotypes was untested"]},{"year":2010,"claim":"The mechanism controlling natural ERAP2 deficiency was identified: a haplotype-specific splice variant (rs2248374) directs nonsense-mediated decay, and homozygous carriers show reduced surface MHC class I, establishing ERAP2 as a non-redundant contributor to antigen presentation in humans.","evidence":"Haplotype analysis, RT-PCR for splice forms, flow cytometry for MHC class I on primary lymphocytes","pmids":["20976248"],"confidence":"High","gaps":["Whether the splicing variant also affects ERAP2 isoform diversity was not explored","Impact on specific peptidome repertoires was uncharacterized"]},{"year":2013,"claim":"The concerted trimming model was extended to viral epitopes: ERAP1 and ERAP2 sequentially use each other's products as substrates, increasing generation of natural HLA-B27 ligands beyond what either enzyme achieves alone.","evidence":"In vitro digestion of viral precursors with mass spectrometry product identification","pmids":["24223975"],"confidence":"Medium","gaps":["Whether sequential processing reflects ordered recruitment or stochastic encounter was unclear","Trimming was studied in vitro, not confirmed in live cells for these substrates"]},{"year":2014,"claim":"Heterodimerization was shown to be more than co-localization: stabilized ERAP1–ERAP2 heterodimers display allosterically enhanced kinetics—improved substrate binding affinity and trimming efficiency—compared to equimolar mixtures of non-interacting enzymes.","evidence":"Stabilized heterodimer production, enzymatic kinetic parameter measurements","pmids":["24928998"],"confidence":"High","gaps":["Structural basis of allosteric communication was unresolved","Whether allosteric modulation is reciprocal (ERAP2 kinetics altered by ERAP1) was not tested"]},{"year":2016,"claim":"The substrate scope of ERAP1/ERAP2 heterodimers was expanded beyond free peptides: the complex trims MHC class I-bound precursor peptides, increasing conformational stability of resulting pMHC complexes and supporting a peptide-editing model.","evidence":"In vitro trimming of HLA-B*08:01-bound N-terminally extended peptides with stability measurements","pmids":["27514473"],"confidence":"High","gaps":["Whether trimming of MHC-bound peptides occurs in the ER lumen was not demonstrated","Contribution of tapasin-mediated editing relative to ERAP trimming was unaddressed"]},{"year":2017,"claim":"Quantitative peptidomics across multiple HLA allotypes established that ERAP2 and ERAP1 exert distinct effects on the immunopeptidome: ERAP2 specifically depletes peptides with N-terminal basic residues, while ERAP1 primarily controls length—and the two enzymes largely act as separate entities in vivo despite their ability to heterodimerize.","evidence":"Label-free quantitative mass spectrometry of HLA-B*27:05, B*51:01, B*40:02, and A*29:02 peptidomes from CRISPR KO or genotype-defined cell lines","pmids":["28063628","31092671","31530632","29769354"],"confidence":"High","gaps":["Relative contributions of heterodimer vs. monomer activity in live cells were not resolved","How ERAP2 effects translate to T cell immunodominance was not systematically tested"]},{"year":2019,"claim":"A secretory function was established: activated macrophages secrete full-length ERAP2, and exogenous ERAP2 reduces HIV-1 replication in PBMCs while enhancing CD8+ T cell activation, revealing an extracellular immunomodulatory role.","evidence":"Mass spectrometry of activated macrophage secretome; recombinant ERAP2 addition to PBMC cultures with viral replication and immune activation assays","pmids":["31379846"],"confidence":"Medium","gaps":["Mechanism by which extracellular ERAP2 activates CD8+ T cells is unknown","Whether the enzymatic activity of secreted ERAP2 is required was not tested"]},{"year":2020,"claim":"A catalytically inactive ERAP2 isoform (Iso3) was discovered to be induced by microbial stimulation; it retains heterodimerization capacity with ERAP1 and wild-type ERAP2, introducing a dominant-negative regulatory mechanism that reshapes the immunopeptidome.","evidence":"RT-PCR, Western blot, and dimerization assays in PBMCs and macrophages stimulated with influenza, LPS, CMV, HIV, SARS-CoV-2","pmids":["32847031"],"confidence":"Medium","gaps":["Whether Iso3 dimerization actually inhibits ERAP1 function in vivo was not directly shown","Structural basis for loss of trimming by Iso3 is uncharacterized"]},{"year":2022,"claim":"Structural determination of ERAP2 with multiple inhibitors revealed a catalytic-site proximal allosteric site governed by His904, providing a molecular framework for selective pharmacological modulation of ERAP2 independent of ERAP1.","evidence":"Crystal structures of ERAP2–inhibitor complexes, site-directed mutagenesis of His904, kinetic analysis","pmids":["35767698","35904863"],"confidence":"High","gaps":["Whether allosteric inhibitors affect ERAP1–ERAP2 heterodimer function is untested","No co-crystal structure of the heterodimer exists"]},{"year":2022,"claim":"A self-modulation mechanism between ERAP1 and ERAP2 was uncovered: ERAP2 preferentially trims <9-mer substrates that simultaneously inhibit ERAP1, while longer substrates preferred by ERAP1 inhibit ERAP2, creating a synergistic length-selection filter.","evidence":"Biochemical enzymatic assays with defined-length peptide substrates","pmids":["36569828"],"confidence":"Medium","gaps":["Whether mutual inhibition operates in the heterodimer complex or only between free enzymes is unknown","In vivo validation of the self-modulation model is lacking"]},{"year":2022,"claim":"An autocatalytically generated short form of ERAP2 was identified in macrophages; it localizes to endosomes and plasma membrane where it binds IRAP, suggesting a function in angiotensin processing outside the ER.","evidence":"Western blot, co-immunoprecipitation with IRAP, co-localization microscopy, autocatalytic cleavage assays in acidic conditions","pmids":["35563348"],"confidence":"Medium","gaps":["Whether short ERAP2 actually cleaves angiotensin substrates is not demonstrated","The physiological trigger for autocatalytic cleavage in vivo is uncharacterized","Single-lab finding without independent replication"]},{"year":2023,"claim":"The regulatory architecture of ERAP2 expression was completed: reciprocal allelic replacement confirmed rs2248374 as the causal splice-regulatory variant, and chromosome conformation capture revealed that disease-associated variants in the LNPEP promoter independently regulate ERAP2 through long-range chromatin contacts.","evidence":"CRISPR reciprocal allelic replacement, allele-specific 3C chromatin conformation capture, reporter assays","pmids":["38190099"],"confidence":"High","gaps":["Whether LNPEP-ERAP2 chromatin contacts are tissue-specific is unknown","Mechanism by which LNPEP promoter variants alter ERAP2 transcription is not molecularly defined"]},{"year":null,"claim":"Key unresolved questions include the structural basis of the ERAP1–ERAP2 heterodimer and whether allosteric communication is bidirectional, the physiological substrate repertoire of the secreted short ERAP2 form, and whether dominant-negative Iso3 dimerization provides a feedback mechanism that calibrates immunopeptidome diversity during infection.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structure of the ERAP1–ERAP2 heterodimer exists","Enzymatic substrates of extracellular/endosomal ERAP2 are undefined","Functional impact of Iso3 on immunopeptidome in vivo is untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,4,5,7,8,10,12]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,3,5,8,10,19]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,1,14]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[14]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[15]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[14]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,5,7,8,11,19]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,3,10]}],"complexes":["ERAP1–ERAP2 heterodimer"],"partners":["ERAP1","IRAP","EPCAM"],"other_free_text":[]},"mechanistic_narrative":"ERAP2 is an endoplasmic reticulum-resident zinc aminopeptidase that trims N-terminal residues from peptide precursors to shape the MHC class I immunopeptidome, with a preference for shorter substrates (<9-mers) and N-terminal basic residues [PMID:15908954, PMID:28063628, PMID:36569828]. It physically heterodimerizes with ERAP1, and this complex exhibits allosterically enhanced trimming efficiency and complementary substrate specificity that together optimize the length and sequence composition of HLA class I ligands across multiple allotypes [PMID:24928998, PMID:27514473, PMID:31092671]. ERAP2 expression is governed by the splice-region variant rs2248374, which directs nonsense-mediated decay of the haplotype B transcript, and by long-range chromatin contacts from the LNPEP promoter that independently modulate transcription [PMID:20976248, PMID:38190099]. Beyond its canonical ER function, an autocatalytically generated short form of ERAP2 is secreted by macrophages, binds IRAP in endosomes, and full-length ERAP2 secreted from activated macrophages modulates immune cell activation [PMID:35563348, PMID:31379846]."},"prefetch_data":{"uniprot":{"accession":"Q6P179","full_name":"Endoplasmic reticulum aminopeptidase 2","aliases":["Leukocyte-derived arginine aminopeptidase","L-RAP"],"length_aa":960,"mass_kda":110.5,"function":"Aminopeptidase that plays a central role in peptide trimming, a step required for the generation of most HLA class I-binding peptides. Peptide trimming is essential to customize longer precursor peptides to fit them to the correct length required for presentation on MHC class I molecules. Preferentially hydrolyzes the basic residues Arg and Lys","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q6P179/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ERAP2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ERAP2","total_profiled":1310},"omim":[{"mim_id":"609497","title":"ENDOPLASMIC RETICULUM AMINOPEPTIDASE 2; ERAP2","url":"https://www.omim.org/entry/609497"},{"mim_id":"609423","title":"HUMAN IMMUNODEFICIENCY VIRUS TYPE 1, SUSCEPTIBILITY TO","url":"https://www.omim.org/entry/609423"},{"mim_id":"606832","title":"ENDOPLASMIC RETICULUM AMINOPEPTIDASE 1; ERAP1","url":"https://www.omim.org/entry/606832"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Golgi apparatus","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"lymphoid 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\"Co-immunoprecipitation (physical association), in vitro peptide digestion assays, cellular antigen presentation assays, in vivo co-localization\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro reconstitution + in vivo functional assay + physical interaction, replicated across multiple experimental approaches in a highly cited foundational paper\",\n      \"pmids\": [\"15908954\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ERAP2 Haplotype B undergoes differential splicing, encoding a truncated protein that is degraded by nonsense-mediated decay (NMD), resulting in ERAP2 deficiency. Haplotype B homozygotes have lower surface MHC class I expression on B cells, demonstrating that naturally occurring ERAP2 deficiency functionally affects MHC class I antigen presentation.\",\n      \"method\": \"Genetic analysis of haplotypes, RT-PCR for splice forms, flow cytometry for surface MHC class I expression in primary lymphocytes with defined ERAP2 genotypes\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (genetics, splicing, functional cell surface assay), strong evidence from population-level and cellular experiments\",\n      \"pmids\": [\"20976248\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ERAP1-ERAP2 dimerization increases peptide-trimming efficiency: stabilized ERAP1-ERAP2 heterodimers produce mature MHC class I epitopes more efficiently than a mix of the two enzymes unable to dimerize. Physical interaction with ERAP2 changes basic enzymatic parameters of ERAP1 and improves its substrate-binding affinity through allosteric effects.\",\n      \"method\": \"Production of stabilized ERAP1-ERAP2 heterodimers, enzymatic assays comparing heterodimers vs. enzyme mixtures unable to dimerize, kinetic parameter measurements\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro reconstitution with stabilized heterodimers and kinetic analysis; functionally rigorous\",\n      \"pmids\": [\"24928998\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ERAP1/ERAP2 heterodimers can trim MHC class I-bound precursor peptides to their correct and final lengths (albeit more slowly than free precursors), and trimming of MHC I-bound precursors by ERAP1/2 increases the conformational stability of MHC I/peptide complexes, supporting a peptide editing model.\",\n      \"method\": \"In vitro trimming assays using ERAP1/2 heterodimers with free and HLA-B*0801-bound N-terminally extended model and natural peptides; conformational stability measurements\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with defined substrates (free and MHC-bound), multiple functional readouts\",\n      \"pmids\": [\"27514473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ERAP1 and ERAP2 act concertedly in trimming viral HLA-B27-restricted peptide precursors: each enzyme can use the degradation products of the other as substrates for new N-terminal trimming, with double enzyme digestions producing increased amounts of natural HLA-B27 ligands compared to single enzyme digestions.\",\n      \"method\": \"In vitro peptide digestion with ERAP1 and/or ERAP2, mass spectrometry identification of products\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro assay with mass spectrometry, single lab, moderate evidence for concerted activity\",\n      \"pmids\": [\"24223975\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ERAP1 and ERAP2 have significant but distinct and largely separate effects on the HLA-B*27 peptidome in human cells: ERAP1 effects relate primarily to peptide length and N-terminal Ala1 frequency, while ERAP2 effects additionally reduce peptides with N-terminal basic residues and lower the affinity of the peptidome. Both enzymes largely act as separate entities in vivo.\",\n      \"method\": \"Quantitative label-free mass spectrometry comparison of HLA-B*27:05 peptidomes from cells with various ERAP1/ERAP2 phenotypes\",\n      \"journal\": \"Journal of autoimmunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — quantitative peptidomics in multiple cell contexts with defined ERAP phenotypes, multiple orthogonal comparisons\",\n      \"pmids\": [\"28063628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ERAP2 alters the HLA-A*29:02 peptidome in a manner distinct from HLA-B*27: presence of ERAP2 increases amounts of peptides >9-mers and alters N-terminal residues toward less ERAP2-susceptible, more hydrophobic residues. Unproductive binding to ERAP2 may protect some peptides from ERAP1 over-trimming.\",\n      \"method\": \"Lentiviral transduction of ERAP2 into ERAP2-negative cell lines, label-free quantitative mass spectrometry of A*29:02 peptidomes\",\n      \"journal\": \"Molecular & cellular proteomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — quantitative peptidomics with controlled ERAP2 expression, replicated in two independent cell line comparisons\",\n      \"pmids\": [\"29769354\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ERAP2 depleted by CRISPR/Cas9 knockout shows functional redundancy with ERAP1 in processing HLA-B*51:01 ligands: in the absence of ERAP1, ERAP2 alone can perform similar and significant processing of B*51:01 ligands. ERAP1 and ERAP2 have distinct but complementary and partially redundant effects on the B*51:01 peptidome, required for its optimization and maximal surface expression.\",\n      \"method\": \"CRISPR/Cas9 knockout of ERAP1, ERAP2, or both; label-free quantitative mass spectrometry of HLA-B*51:01 peptidomes; surface HLA expression measurement\",\n      \"journal\": \"Molecular & cellular proteomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — CRISPR KO with quantitative peptidomics in multiple KO combinations, strong mechanistic conclusions\",\n      \"pmids\": [\"31092671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ERAP2 shapes the natural HLA-B*27:05 ligandome in live cells: in absence of ERAP2, peptides with N-terminal basic residues and minority canonical P2 residues are enriched, and alterations in residue frequencies at P3, P7, and PΩ positions are observed. Additionally, ERAP2-dependent cellular peptides show high similarity to sequences from arthritogenic bacteria including Campylobacter jejuni.\",\n      \"method\": \"CRISPR/Cas9 editing of ERAP2 in HLA-B*27:05-expressing cells, quantitative tandem mass spectrometry of natural ligandome, bioinformatics sequence alignment\",\n      \"journal\": \"Molecular & cellular proteomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — CRISPR KO with quantitative peptidomics, rigorous controls\",\n      \"pmids\": [\"32265295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ERAP2 has substantial influence on the HLA-B*40:02 peptidome: depletion of ERAP2 by CRISPR KO causes major effects on N-terminal residue frequencies (increased basic and small residues, decreased aliphatic/aromatic ones) and quantitative changes in peptide amounts, with ERAP2 affecting the generation/destruction balance of HLA-B*40:02 ligands.\",\n      \"method\": \"CRISPR/Cas9 knockout of ERAP2 in C1R-B*40:02, label-free quantitative mass spectrometry peptidome comparison\",\n      \"journal\": \"Molecular & cellular proteomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — CRISPR KO with quantitative peptidomics\",\n      \"pmids\": [\"31530632\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ERAP2 preferentially trims peptides shorter than 9 residues, while ERAP1 efficiently trims peptides longer than 9 residues. The optimal ligands for either enzyme act as inhibitors of the other: octamers reduce long-peptide trimming by ERAP1, while peptides longer than nonamers inhibit ERAP2 activity. This mutual inhibition constitutes a synergistic self-modulation mechanism shaping the MHC-I peptidome.\",\n      \"method\": \"Biochemical enzymatic assays and proteomic studies with defined peptide substrates, biological verification\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — biochemical enzymatic assays with defined substrates, single lab\",\n      \"pmids\": [\"36569828\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ERAP2 increases the abundance of a specific peptide submotif in the HLA-A29 immunopeptidome that is highly selective for HLA-A29. ERAP2 also imprints internal sequence specificity in the immunopeptidome. The effects of ERAP2 on N-terminal residues of HLA-A29 ligands are shared across HLA allotypes, but the A29-specific motif is uniquely generated in the presence of ERAP2.\",\n      \"method\": \"HLA-A29-based and pan-class I immunopurification, isotope-labeled naturally processed peptide sequencing by mass spectrometry in patient-derived antigen-presenting cells with and without ERAP2\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — quantitative immunopeptidomics in patient-derived cells, replicated finding\",\n      \"pmids\": [\"33717175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Crystal structure of ERAP2 bound to a phenylsulfamoyl benzoic acid inhibitor (compound 61) reveals that the inhibitor binds near the catalytic center of ERAP2 at a distinct site from peptidomimetic inhibitors, and inhibits by an uncompetitive mechanism. His904 in ERAP2 is a key selectivity determinant governing compound binding at the allosteric site; mutation of His904 to alanine reveals a cryptic allosteric site permitting activation of ERAP2 by compound 3.\",\n      \"method\": \"Crystal structure determination of ERAP2-inhibitor complex, enzymatic inhibition assays, site-directed mutagenesis of His904\",\n      \"journal\": \"ACS chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus mutagenesis and kinetic analysis defining mechanism of inhibition and selectivity determinants\",\n      \"pmids\": [\"35767698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Co-crystallization of ERAP2 with three different inhibitors discovered by kinetic target-guided synthesis reveals the binding mode of selective ERAP2 inhibitors; selected analogues engage ERAP2 in cells and inhibit antigen presentation in a cellular context.\",\n      \"method\": \"Kinetic target-guided synthesis, co-crystallization and X-ray structure determination, cellular ERAP2 engagement assays, antigen presentation assays\",\n      \"journal\": \"Angewandte Chemie\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structures with multiple inhibitors, cellular functional validation\",\n      \"pmids\": [\"35904863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A shorter form of ERAP2 is generated in macrophages by autocatalytic cleavage within a distinctive structural motif in an acidic microenvironment, independently of ERAP2 haplotype. This 'short' ERAP2 binds IRAP (insulin-regulated aminopeptidase), and the two molecules are co-expressed in endosomes and on the cell membrane, suggesting a function for ERAP2 outside the ER in the angiotensin system.\",\n      \"method\": \"Western blot characterization of short ERAP2 form, co-immunoprecipitation of ERAP2 short with IRAP, co-localization by microscopy, subcellular fractionation, autocatalytic cleavage assays\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — biochemical characterization plus co-IP and co-localization, single lab\",\n      \"pmids\": [\"35563348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ERAP2 is secreted from activated human monocyte-derived macrophages (MDMs) in response to IFNγ/LPS stimulation. Exogenous recombinant ERAP2-FL reduces HIV-1 viral replication in PBMCs, associated with increased IFNγ and CD69 mRNA expression and increased perforin-expressing CD8+ T cells.\",\n      \"method\": \"Mass spectrometry identification of ERAP2 in secretome of activated MDMs; addition of recombinant ERAP2 to PBMC cultures with p24 viral antigen quantification; flow cytometry and gene expression analysis\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — MS identification of secreted protein plus functional assay, single lab\",\n      \"pmids\": [\"31379846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"EpCAM associates with ERAP2 in breast cancer cells: ERAP2 co-precipitates with EpCAM and co-localizes in the cytoplasm/ER and plasma membrane, suggesting a novel interaction that may regulate EpCAM processing and antigen presentation in cancer.\",\n      \"method\": \"Co-immunoprecipitation followed by mass spectrometry, co-localization by microscopy, in vitro expression in dog pancreas rough microsomes\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP/MS finding with partial follow-up, no functional mechanism established\",\n      \"pmids\": [\"23988446\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ERAP2 plays a role in autophagy and activation of pancreatic stellate cells (PSCs) via the unfolded protein response (UPR) signaling pathway: ERAP2 knockdown by siRNA inhibited UPR-mediated autophagy and led to inactivation of PSCs, attenuating tumor-stromal interactions by inhibiting IL-6 and fibronectin production. In vivo, ERAP2 knockdown suppressed xenografted tumor growth and fibrosis.\",\n      \"method\": \"siRNA knockdown of ERAP2 in PSCs, autophagy and ER stress assays, gene expression microarray, IL-6 and fibronectin measurement, orthotopic xenograft mouse model\",\n      \"journal\": \"Pancreatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with defined cellular and in vivo phenotypes, but mechanism linking ERAP2 to UPR/autophagy is not fully characterized\",\n      \"pmids\": [\"34642112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ERAP2 inhibition in MOLT-4 T lymphoblast leukemia cells induces significant shifts in the MHC class I immunopeptidome: more than 20% of detected peptides are either novel or significantly upregulated, with inhibitor-induced peptides being predominantly 9-mers with sequence motifs and predicted affinity consistent with optimal MHC class I ligands.\",\n      \"method\": \"Selective ERAP2 inhibitor treatment, MHC class I immunopurification, LC-MS/MS peptidomics of MOLT-4 cells\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological inhibition with quantitative peptidomics, single lab\",\n      \"pmids\": [\"35163832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ERAP2 alone, when expressed in ERAP-deficient cells, elicits strong CTL responses toward the Tyrosinase368-376 tumor epitope; ERAP2 also influences recognition of gp100209-217 and enhances T cell recognition of MART-126/27-35 in the absence of ERAP1 expression. In vitro, ERAP1 and ERAP2 differently customize TAP-dependent N-terminally extended epitope precursor peptides.\",\n      \"method\": \"Expression of ERAP2 in ERAP-deficient cells, CTL recognition assays, in vitro peptide trimming assays with TAP-dependent precursors\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional cellular assays plus in vitro trimming, single lab\",\n      \"pmids\": [\"36608422\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A new ERAP2 isoform (ERAP2/Iso3) is expressed from the major haplotype following microbial stimulation (influenza, LPS, CMV, HIV, SARS-CoV-2 antigens) in PBMCs and MDMs. Unlike ERAP2-wt, ERAP2/Iso3 is unable to trim peptides for MHC class I loading but retains the ability to dimerize with both ERAP2-wt and ERAP1-wt, contributing to an alternative cellular immune-peptidome.\",\n      \"method\": \"RT-PCR/Quantigene for isoform mRNA expression, Western blot for protein, dimerization assays, stimulation with multiple pathogens\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — mRNA and protein confirmed, functional trimming and dimerization assessed, single lab\",\n      \"pmids\": [\"32847031\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ERAP2 expression is directly controlled by the splice region variant rs2248374, demonstrated by reciprocal allelic replacement. Additionally, disease-associated variants in the downstream LNPEP gene promoter independently regulate ERAP2 expression through long-range chromatin contacts between LNPEP and ERAP2 promoters, with stronger interactions in patients carrying autoimmune disease-susceptibility alleles.\",\n      \"method\": \"Reciprocal allelic replacement (CRISPR), allele-specific conformation capture (3C) assays measuring chromatin contacts, reporter assays\",\n      \"journal\": \"Cell genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reciprocal allelic replacement plus allele-specific chromatin conformation capture, multiple orthogonal methods establishing cis-regulatory mechanism\",\n      \"pmids\": [\"38190099\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Discovery of potent inhibitors selective for ERAP2 (Ki=100–350 nM) among phosphinic dipeptide analogues; N'-substituted α,β-diaminophosphonates and phosphinates showed selectivity toward ERAP2 only, consistent with the P1 basic substrate-oriented specificity of ERAP2, distinguishing it from ERAP1.\",\n      \"method\": \"In vitro enzymatic inhibition screening of 50 phosphonic/phosphinic acid compounds against ERAP1 and ERAP2, Ki determination\",\n      \"journal\": \"Bioorganic & medicinal chemistry letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — in vitro enzymatic assays with defined inhibitors revealing substrate specificity, single study\",\n      \"pmids\": [\"27390066\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ERAP2 contributes to modulation of neutrophil function when secreted extracellularly: recombinant ERAP2 is internalized by neutrophils and triggers their activation (increased MAC-1+CD66b+, cytokine release), increases migration capacity, autophagy, and phagocytosis activity, and reduces ROS accumulation.\",\n      \"method\": \"Recombinant human ERAP2 supplementation to neutrophil cultures, Western blot for internalization, flow cytometry for activation markers, transwell migration assay, ROS measurement, autophagy assay\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, functional assays with exogenous protein, no molecular mechanism established\",\n      \"pmids\": [\"39839670\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ERAP2 is an ER-resident zinc metalloprotease that trims N-terminal residues from peptide precursors (preferring shorter substrates <9-mers and N-terminal basic residues) to generate optimal MHC class I ligands; it physically associates with ERAP1 to form heterodimers that have superior and complementary peptide-trimming efficiency through allosteric modulation of ERAP1 kinetics, while ERAP2 expression is controlled by a splice-region variant (rs2248374) and by long-range chromatin contacts from the LNPEP promoter, and an autocatalytic short form of ERAP2 is secreted by macrophages where it binds IRAP in endosomes, suggesting additional functions in the renin-angiotensin system beyond ER antigen processing.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ERAP2 is an endoplasmic reticulum-resident zinc aminopeptidase that trims N-terminal residues from peptide precursors to shape the MHC class I immunopeptidome, with a preference for shorter substrates (<9-mers) and N-terminal basic residues [PMID:15908954, PMID:28063628, PMID:36569828]. It physically heterodimerizes with ERAP1, and this complex exhibits allosterically enhanced trimming efficiency and complementary substrate specificity that together optimize the length and sequence composition of HLA class I ligands across multiple allotypes [PMID:24928998, PMID:27514473, PMID:31092671]. ERAP2 expression is governed by the splice-region variant rs2248374, which directs nonsense-mediated decay of the haplotype B transcript, and by long-range chromatin contacts from the LNPEP promoter that independently modulate transcription [PMID:20976248, PMID:38190099]. Beyond its canonical ER function, an autocatalytically generated short form of ERAP2 is secreted by macrophages, binds IRAP in endosomes, and full-length ERAP2 secreted from activated macrophages modulates immune cell activation [PMID:35563348, PMID:31379846].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"The foundational question of whether ERAP2 functions independently or cooperatively with ERAP1 was resolved: the two enzymes form ER-resident heterodimers with complementary specificities required for concerted trimming of MHC class I peptide precursors.\",\n      \"evidence\": \"Co-immunoprecipitation, in vitro peptide digestion, and cellular antigen presentation assays\",\n      \"pmids\": [\"15908954\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and structural basis of the heterodimer were unknown\", \"Whether dimerization alters enzymatic kinetics was not addressed\", \"In vivo relevance to specific HLA allotypes was untested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"The mechanism controlling natural ERAP2 deficiency was identified: a haplotype-specific splice variant (rs2248374) directs nonsense-mediated decay, and homozygous carriers show reduced surface MHC class I, establishing ERAP2 as a non-redundant contributor to antigen presentation in humans.\",\n      \"evidence\": \"Haplotype analysis, RT-PCR for splice forms, flow cytometry for MHC class I on primary lymphocytes\",\n      \"pmids\": [\"20976248\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the splicing variant also affects ERAP2 isoform diversity was not explored\", \"Impact on specific peptidome repertoires was uncharacterized\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"The concerted trimming model was extended to viral epitopes: ERAP1 and ERAP2 sequentially use each other's products as substrates, increasing generation of natural HLA-B27 ligands beyond what either enzyme achieves alone.\",\n      \"evidence\": \"In vitro digestion of viral precursors with mass spectrometry product identification\",\n      \"pmids\": [\"24223975\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether sequential processing reflects ordered recruitment or stochastic encounter was unclear\", \"Trimming was studied in vitro, not confirmed in live cells for these substrates\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Heterodimerization was shown to be more than co-localization: stabilized ERAP1–ERAP2 heterodimers display allosterically enhanced kinetics—improved substrate binding affinity and trimming efficiency—compared to equimolar mixtures of non-interacting enzymes.\",\n      \"evidence\": \"Stabilized heterodimer production, enzymatic kinetic parameter measurements\",\n      \"pmids\": [\"24928998\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of allosteric communication was unresolved\", \"Whether allosteric modulation is reciprocal (ERAP2 kinetics altered by ERAP1) was not tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"The substrate scope of ERAP1/ERAP2 heterodimers was expanded beyond free peptides: the complex trims MHC class I-bound precursor peptides, increasing conformational stability of resulting pMHC complexes and supporting a peptide-editing model.\",\n      \"evidence\": \"In vitro trimming of HLA-B*08:01-bound N-terminally extended peptides with stability measurements\",\n      \"pmids\": [\"27514473\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether trimming of MHC-bound peptides occurs in the ER lumen was not demonstrated\", \"Contribution of tapasin-mediated editing relative to ERAP trimming was unaddressed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Quantitative peptidomics across multiple HLA allotypes established that ERAP2 and ERAP1 exert distinct effects on the immunopeptidome: ERAP2 specifically depletes peptides with N-terminal basic residues, while ERAP1 primarily controls length—and the two enzymes largely act as separate entities in vivo despite their ability to heterodimerize.\",\n      \"evidence\": \"Label-free quantitative mass spectrometry of HLA-B*27:05, B*51:01, B*40:02, and A*29:02 peptidomes from CRISPR KO or genotype-defined cell lines\",\n      \"pmids\": [\"28063628\", \"31092671\", \"31530632\", \"29769354\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contributions of heterodimer vs. monomer activity in live cells were not resolved\", \"How ERAP2 effects translate to T cell immunodominance was not systematically tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"A secretory function was established: activated macrophages secrete full-length ERAP2, and exogenous ERAP2 reduces HIV-1 replication in PBMCs while enhancing CD8+ T cell activation, revealing an extracellular immunomodulatory role.\",\n      \"evidence\": \"Mass spectrometry of activated macrophage secretome; recombinant ERAP2 addition to PBMC cultures with viral replication and immune activation assays\",\n      \"pmids\": [\"31379846\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which extracellular ERAP2 activates CD8+ T cells is unknown\", \"Whether the enzymatic activity of secreted ERAP2 is required was not tested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"A catalytically inactive ERAP2 isoform (Iso3) was discovered to be induced by microbial stimulation; it retains heterodimerization capacity with ERAP1 and wild-type ERAP2, introducing a dominant-negative regulatory mechanism that reshapes the immunopeptidome.\",\n      \"evidence\": \"RT-PCR, Western blot, and dimerization assays in PBMCs and macrophages stimulated with influenza, LPS, CMV, HIV, SARS-CoV-2\",\n      \"pmids\": [\"32847031\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether Iso3 dimerization actually inhibits ERAP1 function in vivo was not directly shown\", \"Structural basis for loss of trimming by Iso3 is uncharacterized\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Structural determination of ERAP2 with multiple inhibitors revealed a catalytic-site proximal allosteric site governed by His904, providing a molecular framework for selective pharmacological modulation of ERAP2 independent of ERAP1.\",\n      \"evidence\": \"Crystal structures of ERAP2–inhibitor complexes, site-directed mutagenesis of His904, kinetic analysis\",\n      \"pmids\": [\"35767698\", \"35904863\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether allosteric inhibitors affect ERAP1–ERAP2 heterodimer function is untested\", \"No co-crystal structure of the heterodimer exists\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"A self-modulation mechanism between ERAP1 and ERAP2 was uncovered: ERAP2 preferentially trims <9-mer substrates that simultaneously inhibit ERAP1, while longer substrates preferred by ERAP1 inhibit ERAP2, creating a synergistic length-selection filter.\",\n      \"evidence\": \"Biochemical enzymatic assays with defined-length peptide substrates\",\n      \"pmids\": [\"36569828\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether mutual inhibition operates in the heterodimer complex or only between free enzymes is unknown\", \"In vivo validation of the self-modulation model is lacking\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"An autocatalytically generated short form of ERAP2 was identified in macrophages; it localizes to endosomes and plasma membrane where it binds IRAP, suggesting a function in angiotensin processing outside the ER.\",\n      \"evidence\": \"Western blot, co-immunoprecipitation with IRAP, co-localization microscopy, autocatalytic cleavage assays in acidic conditions\",\n      \"pmids\": [\"35563348\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether short ERAP2 actually cleaves angiotensin substrates is not demonstrated\", \"The physiological trigger for autocatalytic cleavage in vivo is uncharacterized\", \"Single-lab finding without independent replication\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"The regulatory architecture of ERAP2 expression was completed: reciprocal allelic replacement confirmed rs2248374 as the causal splice-regulatory variant, and chromosome conformation capture revealed that disease-associated variants in the LNPEP promoter independently regulate ERAP2 through long-range chromatin contacts.\",\n      \"evidence\": \"CRISPR reciprocal allelic replacement, allele-specific 3C chromatin conformation capture, reporter assays\",\n      \"pmids\": [\"38190099\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether LNPEP-ERAP2 chromatin contacts are tissue-specific is unknown\", \"Mechanism by which LNPEP promoter variants alter ERAP2 transcription is not molecularly defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of the ERAP1–ERAP2 heterodimer and whether allosteric communication is bidirectional, the physiological substrate repertoire of the secreted short ERAP2 form, and whether dominant-negative Iso3 dimerization provides a feedback mechanism that calibrates immunopeptidome diversity during infection.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structure of the ERAP1–ERAP2 heterodimer exists\", \"Enzymatic substrates of extracellular/endosomal ERAP2 are undefined\", \"Functional impact of Iso3 on immunopeptidome in vivo is untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 4, 5, 7, 8, 10, 12]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 3, 5, 8, 10, 19]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 1, 14]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [14]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [15]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [14]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 5, 7, 8, 11, 19]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 3, 10]}\n    ],\n    \"complexes\": [\n      \"ERAP1–ERAP2 heterodimer\"\n    ],\n    \"partners\": [\n      \"ERAP1\",\n      \"IRAP\",\n      \"EPCAM\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}