{"gene":"PSMB10","run_date":"2026-04-28T19:45:45","timeline":{"discoveries":[{"year":1996,"finding":"MECL-1 (LMP10/PSMB10) was identified as the third IFN-gamma-inducible proteasome beta-type subunit. Upon IFN-gamma stimulation, LMP10 (along with LMP2 and LMP7) is incorporated into proteasomes while constitutive counterparts (LMP9, LMP17, LMP19) are displaced; MECL-1 was shown to be the product of the previously cloned MECL-1 gene and to harbor most or all catalytic sites of the proteasome.","method":"2D gel electrophoresis of IFN-gamma-treated cell lysates, Northern blot, protein fractionation of proteasome complexes","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal biochemical methods, foundational identification study replicated across subsequent work","pmids":["8786291"],"is_preprint":false},{"year":1997,"finding":"The incorporation of MECL-1 (PSMB10) into the 20S proteasome requires LMP2; conversely, LMP2 incorporation is strongly enhanced by MECL-1. MECL-1 replaces the constitutive homologous subunit Z. This obligatory co-incorporation of MECL-1 and LMP2 occurs at the level of proteasome precursor formation, indicating concerted assembly of IFN-gamma-inducible subunits encoded inside and outside the MHC.","method":"Cotransfection experiments, immunoprecipitation of 20S proteasome complexes, Western blot analysis of subunit composition","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP with cotransfection, replicated by multiple subsequent studies","pmids":["9256419"],"is_preprint":false},{"year":1997,"finding":"Mouse MECL-1 (PSMB10) and its constitutive homolog MC14 show reciprocal tissue expression: MECL-1 mRNA is highest in thymus, lymph nodes, and spleen, while MC14 predominates in tissues with low MECL-1. This reciprocal pattern mirrors that of LMP2/delta and LMP7/MB1 pairs, and the protein composition of purified 20S proteasomes from liver, thymus, and lung reflects this RNA expression.","method":"Northern blot analysis, 20S proteasome purification and subunit protein composition analysis from multiple tissues","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — proteasome purification plus RNA blots, consistent tissue-level findings","pmids":["9174609"],"is_preprint":false},{"year":1999,"finding":"The MECL-1 (PSMB10) active site is responsible for the trypsin-like activity of the proteasome. A catalytically inactive mutant MECL-1 (active-site mutation) was incorporated normally into cytosolic proteasomes, replacing the constitutive MC14 subunit, but its prosequence removal was incomplete (indicating autocatalytic processing). Absence of the MC14/MECL-1 active sites specifically abrogated trypsin-like proteolytic activity without affecting other catalytic activities, and cleavage specificity is conserved between mammalian and yeast proteasomes.","method":"Site-directed mutagenesis of catalytic residue, stable cell line generation, proteasome purification, peptidase activity assays","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 1 — active-site mutagenesis with direct enzymatic readout, conservation shown across species","pmids":["10413086"],"is_preprint":false},{"year":2000,"finding":"Overexpression of all three immunoproteasome subunits (LMP2, LMP7, MECL-1/PSMB10) in triple transfectants markedly enhanced MHC class I-restricted presentation of the LCMV NP118 epitope. In vitro, immunoproteasomes generated higher amounts of 11- and 12-mer precursor fragments containing the NP118 epitope compared to constitutive proteasomes, demonstrating that MECL-1 inclusion alters antigen processing specificity.","method":"Triple transfection of immunosubunits, T cell epitope presentation assay, in vitro proteasome digestion assay with peptide fragment analysis","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — functional antigen presentation assay combined with in vitro digestion, multiple orthogonal methods","pmids":["10878350"],"is_preprint":false},{"year":2006,"finding":"T cells from double knockout mice lacking both MECL-1 (PSMB10) and LMP7 hyperproliferate in vitro in response to polyclonal mitogens, with accelerated cell cycling in both CD4+ and CD8+ subsets. This hyperproliferation is not observed in single knockouts, and in vivo there are increased numbers of central memory CD8+ T cells, implicating immunoproteasomes in T cell proliferation control beyond MHC class I antigen processing.","method":"Double knockout mouse model, mitogen stimulation assay, flow cytometry for cell cycling and T cell subsets, in vivo phenotyping","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with defined cellular phenotype, multiple T cell subsets analyzed","pmids":["16547243"],"is_preprint":false},{"year":2011,"finding":"Adenovirus E1A directly binds MECL-1 (PSMB10) through its N-terminal region and conserved region 3, while binding poorly to the constitutive β2 subunit. E1A causes downregulation of MECL-1 (and LMP2 and LMP7) expression induced by IFN-gamma, and this downregulation is mediated by reduced IFN-gamma-stimulated STAT1 phosphorylation.","method":"Co-immunoprecipitation, cotransfection, Western blot, binding domain mapping","journal":"Virology","confidence":"Medium","confidence_rationale":"Tier 2 — direct binding demonstrated by Co-IP with domain mapping, single lab","pmids":["22018786"],"is_preprint":false},{"year":2012,"finding":"LMP7 and MECL-1 (PSMB10) jointly regulate cytokine expression (IFN-gamma, IL-4, IL-10, IL-2Rβ, GATA3, and t-bet) in activated splenocytes, while other cytokines (IL-2, IL-13, TNF-alpha, IL-2Rα) are regulated by the proteasome independently of LMP7/MECL-1.","method":"LMP7/MECL1-null mouse, splenocyte activation with PMA/ionomycin, quantitative RT-PCR for cytokine mRNAs, lactacystin inhibitor treatment","journal":"Pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO with defined transcriptional phenotype, but single lab","pmids":["22398747"],"is_preprint":false},{"year":2017,"finding":"Knockout of immunoproteasome subunit β2i (PSMB10) in DOCA/salt hypertensive mice attenuates cardiac fibrosis and inflammation. Mechanistically, β2i KO inhibits IκBα/NF-κB and TGF-β1/Smad2/3 signaling pathways, reducing expression of collagen I, collagen III, α-SMA, IL-1β, IL-6, and TNF-α.","method":"β2i knockout mouse model, DOCA/salt hypertension model, echocardiography, histological staining, qRT-PCR, Western blot","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO with defined pathway inhibition and cardiac phenotype, single lab","pmids":["28478040"],"is_preprint":false},{"year":2018,"finding":"PSMB10 (β2i/LMP10) promotes PTEN degradation and AKT1 activation in atrial tissue during angiotensin II stimulation, which activates IKKβ and drives ubiquitin-mediated IκBα degradation and NF-κB target gene expression (IL-1β, IL-6, NOX2, NOX4, CX43), leading to atrial fibrosis and reactive oxygen species production. PSMB10 KO mice are protected from Ang II-induced atrial fibrillation while AAV9-PSMB10 overexpression aggravates it.","method":"PSMB10 knockout mice, rAAV9-PSMB10 overexpression, Ang II infusion model, IKKβ inhibitor (IMD-0354), Western blot for pathway components, proteasome activity assay","journal":"Hypertension","confidence":"High","confidence_rationale":"Tier 2 — genetic KO and overexpression with pharmacological rescue, mechanistic pathway dissection","pmids":["29507100"],"is_preprint":false},{"year":2018,"finding":"LMP10 (PSMB10) promotes PTEN degradation and activation of AKT/IKK signaling in retinal cells during Ang II stimulation, leading to IκBα phosphorylation and degradation and NF-κB target gene activation, causing hypertensive retinopathy with increased vascular permeability, ROS production, and inflammation.","method":"LMP10 knockout mice, intravitreal rAAV2-LMP10 injection, IKKβ inhibitor (IMD-0354), pathological staining, proteasome trypsin-like activity assay, Western blot","journal":"Redox biology","confidence":"High","confidence_rationale":"Tier 2 — genetic KO plus overexpression with pharmacological intervention, multiple orthogonal readouts","pmids":["29499566"],"is_preprint":false},{"year":2019,"finding":"PSMB10 interacts directly with classical swine fever virus NS3 protein (confirmed by Co-IP, GST pulldown, and confocal microscopy). PSMB10 overexpression inhibits CSFV replication and promotes ubiquitin-proteasome-dependent degradation of NS3. Additionally, PSMB10 restores MHC class I antigen presentation that CSFV had suppressed.","method":"Yeast two-hybrid screening, co-immunoprecipitation, GST pulldown, laser confocal microscopy, overexpression and knockdown of PSMB10, viral replication assay","journal":"Virology","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal binding assays (Y2H, Co-IP, pulldown, imaging) with functional validation","pmids":["31493657"],"is_preprint":false},{"year":2019,"finding":"Crystal structures of β2c- and β2i (PSMB10)-humanized yeast proteasomes with selective inhibitors LU-002c and LU-002i reveal significant differences in the substrate-binding channels of β2c and β2i that underlie subunit selectivity, enabling rational design of compounds with 40-45-fold selectivity for each subunit.","method":"X-ray crystallography of inhibitor-proteasome co-crystals, activity-based protein profiling, yeast mutagenesis, organic synthesis and biochemical screening","journal":"Journal of medicinal chemistry","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with mutagenesis and functional validation, multiple orthogonal methods","pmids":["30657666"],"is_preprint":false},{"year":2020,"finding":"LMP10 (PSMB10) deletion attenuates atherosclerosis in ApoE KO mice by shifting macrophage polarization toward M2 and reducing NF-κB activation (decreased IκBα degradation). Myeloid-specific deletion via bone marrow transplantation recapitulates this phenotype. In vitro, LMP10 deletion blunts macrophage polarization and ox-LDL-induced foam cell formation.","method":"LMP10 KO mice, ApoE KO atherosclerosis model, bone marrow transplantation, flow cytometry for macrophage polarization, in vitro macrophage culture, Western blot","journal":"Frontiers in cell and developmental biology","confidence":"High","confidence_rationale":"Tier 2 — cell-type specific KO via BMT, in vitro and in vivo orthogonal approaches","pmids":["33195259"],"is_preprint":false},{"year":2020,"finding":"LMP10 (PSMB10) KO in Ang II-infused mice promotes autophagic degradation of IGF1R and gp130, reducing downstream phosphorylation of AKT, mTOR, STAT3, and ERK1/2, leading to attenuated cardiac hypertrophic remodeling. In vitro knockdown of LMP10 increases LC3II/I ratio (autophagy marker) and promotes IGF1R/gp130 degradation; chloroquine (autophagy inhibitor) reverses this effect.","method":"LMP10 KO mice, Ang II infusion, echocardiography, Western blot for signaling components, siRNA knockdown, autophagy inhibitor treatment","journal":"Frontiers in physiology","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO with mechanistic rescue by autophagy inhibition, single lab","pmids":["32581853"],"is_preprint":false},{"year":2021,"finding":"Triple knockout of all three immunoproteasome catalytic subunits (β1i/LMP2, β2i/MECL-1/PSMB10, β5i/LMP7) impairs control of Toxoplasma gondii infection, reducing dendritic cell, monocyte, and CD8+ T cell numbers, impairing IFN-gamma/TNF/iNOS production, altering T cell differentiation, elevating apoptosis of microglia and monocytes, and diminishing STAT3 downstream signaling.","method":"Triple immunoproteasome KO mice, T. gondii infection model, flow cytometry, STAT3 signaling analysis, cytokine measurement","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO with multiple cellular readouts, but triple KO cannot isolate PSMB10-specific contribution","pmids":["33968021"],"is_preprint":false},{"year":2023,"finding":"β2i (PSMB10) KO in mice subjected to cardiac I/R injury results in excessive mitochondrial fission due to Mfn1/2 and Drp1 imbalance. Mechanistically, I/R reduces β2i expression and activity, which increases Parkin E3 ligase expression and promotes ubiquitin-dependent degradation of mitofusin 1/2 (Mfn1/2), causing mitochondrial fragmentation. Cardiac overexpression of β2i via rAAV9 ameliorates I/R injury.","method":"β2i KO mice, rAAV9-β2i overexpression, cardiac I/R model, electron microscopy for mitochondrial morphology, Western blot for Parkin/Mfn1/2/Drp1, infarct size measurement","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO plus overexpression with mechanistic pathway identified, single lab","pmids":["37501008"],"is_preprint":false},{"year":2024,"finding":"A heterozygous dominant-negative PSMB10 variant (G201R) markedly reduces immunoproteasome protein expression (PSMB9 and PSMB10) in PBMCs, EBV-B cells, and fibroblasts. PSMB10 is expressed in cortical and medullary thymic epithelial cell subsets (per scRNA-seq). The mutation impairs positive selection of CD8 T cells, generation of T cell receptor diversity, and negative selection of autoreactive T cells, causing severe combined immunodeficiency and Omenn syndrome.","method":"Immunoblotting, flow cytometry, artificial thymic organoid T-cell development assay, human thymus single-cell RNA sequencing, immunophenotyping","journal":"The Journal of allergy and clinical immunology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including scRNA-seq, functional thymic organoid assay, and protein expression analysis","pmids":["39734035"],"is_preprint":false},{"year":2025,"finding":"PSMB10 maintains stemness of chemotherapy-resistant leukemia stem cells by inhibiting senescence and cytotoxic T lymphocyte killing. Mechanistically, PSMB10 downregulation boosts SLC22A16-mediated drug endocytosis and induces chemotherapy-mediated senescence via the RPL6/RPS6-MDM2-P21 pathway. Additionally, PSMB10 promotes MHC-I protein degradation to enable immune escape from CTL killing. Genetic inactivation of PSMB10 in vivo reduces human LSC frequency 19-fold and drug-resistant mouse LSC frequency 7.6-fold.","method":"siRNA/lentivirus knockdown, co-immunoprecipitation, luciferase reporter assays, polysome profiling, quantitative proteomics, xenograft and syngeneic BMT mouse models, flow cytometry","journal":"Journal of experimental & clinical cancer research","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal mechanistic methods with in vivo validation","pmids":["40462177"],"is_preprint":false},{"year":2026,"finding":"A dominant-negative PSMB10 p.G209R mutation disrupts immunoproteasome assembly and function, leading to defective viral sensing and antigen presentation in IFN-treated fibroblasts, causing severe T lymphopenia at birth. Molecular modeling and biochemical studies confirmed impaired immunoproteasome assembly. Despite this, the patient recovered normal naïve T cell counts and T cell receptor diversity within the first year of life.","method":"Molecular modeling, proteomics, transcriptomics, ex vivo T lymphopoiesis, immunoproteasome assembly and function assays","journal":"Journal of human immunity","confidence":"Medium","confidence_rationale":"Tier 2 — molecular modeling with biochemical confirmation, single patient/lab","pmids":["41971628"],"is_preprint":false}],"current_model":"PSMB10 (β2i/MECL-1/LMP10) is an IFN-gamma-inducible catalytic beta subunit of the immunoproteasome whose incorporation requires obligatory co-assembly with LMP2, replaces the constitutive Z/MC14 subunit, provides the trypsin-like proteolytic activity of the complex, and alters antigen processing to enhance MHC class I peptide presentation; beyond antigen presentation, PSMB10 promotes NF-κB signaling through PTEN degradation and IκBα ubiquitination, regulates mitochondrial dynamics by controlling Parkin-dependent Mfn1/2 degradation, prevents autophagy-dependent clearance of pro-hypertrophic receptors (IGF1R, gp130), and maintains leukemia stem cell stemness through the RPL6/RPS6-MDM2-P21 senescence pathway and MHC-I degradation-mediated immune escape."},"narrative":{"teleology":[{"year":1996,"claim":"The identity of the third IFN-γ-inducible proteasome catalytic subunit was unknown; identification of MECL-1/PSMB10 as an exchangeable β-type subunit established the full complement of immunoproteasome catalytic subunits.","evidence":"2D gel electrophoresis and Northern blot of IFN-γ-treated cell lysates with proteasome fractionation","pmids":["8786291"],"confidence":"High","gaps":["Catalytic specificity of the MECL-1 active site was not yet defined","Tissue-level expression pattern not resolved"]},{"year":1997,"claim":"How immunoproteasome subunits encoded at different genomic loci are coordinately assembled was unclear; demonstration that MECL-1 incorporation requires LMP2 co-incorporation during precursor formation established the obligatory cooperative assembly rule and identified the constitutive β2 subunit Z as the displaced counterpart.","evidence":"Cotransfection, immunoprecipitation of 20S proteasome complexes, tissue-level RNA and protein analysis across mouse organs","pmids":["9256419","9174609"],"confidence":"High","gaps":["Structural basis of the LMP2-MECL-1 cooperative assembly not resolved","Whether assembly cooperativity is absolute or quantitative in all cell types"]},{"year":1999,"claim":"The specific catalytic activity contributed by the β2i active site was undefined; active-site mutagenesis showed that MECL-1 provides the trypsin-like activity of the proteasome, with conservation from yeast to mammals.","evidence":"Site-directed mutagenesis of catalytic Thr residue, stable cell lines, peptidase activity assays on purified proteasomes","pmids":["10413086"],"confidence":"High","gaps":["In vivo substrate repertoire of the trypsin-like site not identified","Structural basis for cleavage preference not yet available"]},{"year":2000,"claim":"Whether immunoproteasome incorporation actually alters antigen processing output was unresolved; triple transfection of LMP2/LMP7/MECL-1 demonstrated enhanced MHC class I epitope generation both in cellulo and in vitro, directly linking immunoproteasome composition to antigen presentation quality.","evidence":"Triple transfection of immunosubunits, T-cell epitope presentation assay, in vitro proteasome digestion with fragment analysis","pmids":["10878350"],"confidence":"High","gaps":["Individual contribution of MECL-1 versus LMP2/LMP7 to altered cleavage not separated","Epitope repertoire breadth analysis limited to one viral epitope"]},{"year":2006,"claim":"Whether immunoproteasome subunits have functions beyond antigen presentation was uncertain; MECL-1/LMP7 double-KO mice revealed cell-intrinsic T-cell hyperproliferation and altered memory differentiation, establishing a non-antigen-processing role in T-cell homeostasis.","evidence":"Double KO mouse model, mitogen stimulation, flow cytometry of T-cell subsets","pmids":["16547243"],"confidence":"High","gaps":["Individual contribution of MECL-1 versus LMP7 not resolved","Molecular target of proliferation control not identified"]},{"year":2011,"claim":"How adenovirus evades immunoproteasome-mediated antigen presentation was unknown; E1A was shown to directly bind MECL-1 and downregulate all three immunosubunits by suppressing STAT1 phosphorylation, revealing a viral immune evasion mechanism targeting PSMB10.","evidence":"Co-immunoprecipitation, cotransfection, binding domain mapping","pmids":["22018786"],"confidence":"Medium","gaps":["Whether E1A-MECL-1 interaction is direct (no in vitro reconstitution)","Functional consequence for viral immune evasion in vivo not tested"]},{"year":2018,"claim":"The signaling mechanism by which PSMB10 promotes inflammation in cardiovascular tissue was unknown; KO and overexpression studies in atrial and retinal models established that PSMB10 drives PTEN degradation, activating the AKT–IKKβ–NF-κB axis to promote fibrosis, ROS, and inflammation.","evidence":"PSMB10 KO mice, rAAV9 overexpression, Ang II infusion, IKKβ inhibitor rescue, Western blot pathway analysis in cardiac and retinal tissues","pmids":["29507100","29499566"],"confidence":"High","gaps":["Direct ubiquitination mechanism for PTEN by immunoproteasome not shown","Whether PTEN is a direct substrate or degraded indirectly through other E3 ligases"]},{"year":2019,"claim":"Structural determinants of β2i versus β2c substrate-binding channel selectivity were undefined; co-crystal structures of humanized yeast proteasomes with selective inhibitors revealed specific channel differences enabling rational design of β2i-selective compounds.","evidence":"X-ray crystallography of inhibitor-proteasome co-crystals, activity-based protein profiling, yeast mutagenesis","pmids":["30657666"],"confidence":"High","gaps":["No structure of fully human immunoproteasome at this site","In vivo pharmacology of selective β2i inhibitors not validated"]},{"year":2020,"claim":"How PSMB10 influences cardiac hypertrophy and macrophage biology was not understood; KO studies demonstrated that PSMB10 loss promotes autophagic degradation of IGF1R/gp130 attenuating hypertrophy, and shifts macrophage polarization toward M2 to reduce atherosclerosis through decreased NF-κB activation.","evidence":"LMP10 KO mice with Ang II or ApoE-KO atherosclerosis models, bone marrow transplantation, autophagy inhibitor rescue, flow cytometry","pmids":["32581853","33195259"],"confidence":"Medium","gaps":["Mechanism linking immunoproteasome to autophagy regulation not fully delineated","Whether macrophage polarization shift is cell-autonomous confirmed only by BMT, not conditional KO"]},{"year":2023,"claim":"How PSMB10 intersects with mitochondrial quality control was unknown; ischemia-reperfusion studies showed that PSMB10 loss increases Parkin expression, accelerating ubiquitin-dependent Mfn1/2 degradation and causing excessive mitochondrial fission.","evidence":"β2i KO mice, rAAV9 overexpression, cardiac I/R model, electron microscopy, Western blot for Parkin/Mfn1/2/Drp1","pmids":["37501008"],"confidence":"Medium","gaps":["Direct mechanism by which immunoproteasome regulates Parkin expression not shown","Single lab finding awaiting independent confirmation"]},{"year":2024,"claim":"Whether PSMB10 mutations cause human immunodeficiency was unresolved; a dominant-negative G201R variant was shown to impair immunoproteasome assembly, disrupt thymic T-cell selection, and cause severe combined immunodeficiency with Omenn syndrome.","evidence":"Immunoblotting, flow cytometry, artificial thymic organoid assay, human thymus scRNA-seq, immunophenotyping","pmids":["39734035"],"confidence":"High","gaps":["Structural basis of G201R dominant-negative effect not determined at atomic resolution","Whether other PSMB10 variants cause milder immunodeficiency phenotypes"]},{"year":2025,"claim":"The role of PSMB10 in leukemia stem cell maintenance was unknown; PSMB10 was found to suppress senescence through the RPL6/RPS6–MDM2–P21 pathway and promote immune escape via MHC-I degradation, maintaining chemotherapy-resistant LSC stemness.","evidence":"siRNA/lentivirus knockdown, co-IP, polysome profiling, quantitative proteomics, xenograft and syngeneic mouse models","pmids":["40462177"],"confidence":"High","gaps":["Whether PSMB10 directly degrades MHC-I or acts through intermediate substrates not resolved","Therapeutic window for PSMB10 targeting in AML patients not established"]},{"year":null,"claim":"Key unresolved questions include the full in vivo substrate repertoire of the β2i trypsin-like activity, the direct mechanism linking immunoproteasome activity to autophagy regulation and Parkin expression, and whether selective β2i inhibitors can be exploited therapeutically in cancer or autoimmunity without compromising infection defense.","evidence":"","pmids":[],"confidence":"Low","gaps":["No comprehensive substrate identification by proteomics for β2i-specific cleavage events","Mechanism of PSMB10-dependent autophagy regulation remains indirect","Therapeutic index of β2i-selective inhibition in immune-competent organisms unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,3,4,9,10,11,12,18]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[3,12]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1,3]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4,5,7,11,15,17,18]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1,3,12]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[8,9,10,13,14]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[9,10,13,16,18]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[14]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[18]}],"complexes":["20S immunoproteasome","26S immunoproteasome"],"partners":["PSMB9","PSMB8","PTEN","PRKN","MFN1","MFN2","RPL6","RPS6"],"other_free_text":[]},"mechanistic_narrative":"PSMB10 (β2i/MECL-1/LMP10) is an IFN-γ-inducible catalytic subunit of the immunoproteasome that replaces the constitutive β2 (Z/MC14) subunit, provides the trypsin-like proteolytic activity of the 20S complex, and requires obligatory co-incorporation with LMP2 during proteasome precursor assembly [PMID:8786291, PMID:9256419, PMID:10413086]. Incorporation of PSMB10 together with LMP2 and LMP7 alters cleavage specificity to enhance generation of MHC class I-restricted peptide epitopes, and dominant-negative PSMB10 mutations that disrupt immunoproteasome assembly cause severe combined immunodeficiency and Omenn syndrome through impaired thymic T-cell selection [PMID:10878350, PMID:39734035]. Beyond antigen processing, PSMB10 promotes NF-κB signaling by driving PTEN degradation and IκBα turnover in cardiovascular and retinal tissues, regulates mitochondrial dynamics by controlling Parkin-dependent Mfn1/2 degradation during ischemia-reperfusion injury, and maintains leukemia stem cell stemness through MHC-I degradation-mediated immune evasion and suppression of RPL6/RPS6–MDM2–P21 senescence [PMID:29507100, PMID:37501008, PMID:40462177]. Loss of PSMB10 also shifts macrophage polarization toward an M2 phenotype and attenuates atherosclerosis, while combined loss with LMP7 deregulates T-cell proliferation and cytokine expression [PMID:33195259, PMID:16547243]."},"prefetch_data":{"uniprot":{"accession":"P40306","full_name":"Proteasome subunit beta type-10","aliases":["Low molecular mass protein 10","Macropain subunit MECl-1","Multicatalytic endopeptidase complex subunit MECl-1","Proteasome MECl-1","Proteasome subunit beta-2i"],"length_aa":273,"mass_kda":28.9,"function":"The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity. This subunit is involved in antigen processing to generate class I binding peptides","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/P40306/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PSMB10","classification":"Not Classified","n_dependent_lines":6,"n_total_lines":1208,"dependency_fraction":0.004966887417218543},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ACTR2","stoichiometry":0.2},{"gene":"RPL27","stoichiometry":0.2},{"gene":"ACTB","stoichiometry":0.2},{"gene":"ITPR3","stoichiometry":0.2},{"gene":"RBM39","stoichiometry":0.2},{"gene":"PSME1","stoichiometry":0.2},{"gene":"PHF10","stoichiometry":0.2},{"gene":"CPSF6","stoichiometry":0.2},{"gene":"MYH9","stoichiometry":0.2},{"gene":"MYH10","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PSMB10","total_profiled":1310},"omim":[{"mim_id":"620807","title":"IMMUNODEFICIENCY 121 WITH AUTOINFLAMMATION; IMD121","url":"https://www.omim.org/entry/620807"},{"mim_id":"619175","title":"PROTEASOME-ASSOCIATED AUTOINFLAMMATORY SYNDROME 5; PRAAS5","url":"https://www.omim.org/entry/619175"},{"mim_id":"611137","title":"PROTEASOME SUBUNIT, BETA-TYPE, 11; PSMB11","url":"https://www.omim.org/entry/611137"},{"mim_id":"256040","title":"PROTEASOME-ASSOCIATED AUTOINFLAMMATORY SYNDROME 1; PRAAS1","url":"https://www.omim.org/entry/256040"},{"mim_id":"176847","title":"PROTEASOME 20S SUBUNIT, BETA-TYPE, 10; PSMB10","url":"https://www.omim.org/entry/176847"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"lymphoid 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incorporation into the 20S proteasome is directly dependent on LMP2 expression, and conversely LMP2 incorporation is strongly enhanced by MECL-1; cotransfection experiments showed MECL-1 replaces the constitutive subunit Z, and LMP2 is required for MECL-1 incorporation at the level of proteasome precursor formation, ensuring concerted incorporation of both IFN-γ-inducible subunits.\",\n      \"method\": \"Cotransfection experiments, proteasome complex immunoprecipitation/purification, Western blot\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-expression/incorporation assays, replicated finding, highly cited foundational paper\",\n      \"pmids\": [\"9256419\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"MECL-1 (LMP10/PSMB10) is identified as the third IFN-γ-inducible proteasome beta-type subunit; IFN-γ increases MECL-1 transcription and its incorporation into proteasomes, concurrently reducing incorporation of constitutive subunits LMP-9, LMP-17, and LMP-19.\",\n      \"method\": \"Protein identification, Northern blot, proteasome fractionation\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — original identification with multiple biochemical methods, highly cited\",\n      \"pmids\": [\"8786291\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Catalytically inactive mutant MECL-1 (PSMB10) is incorporated into cytosolic proteasomes replacing constitutive MC14, but its prosequence removal is incomplete, indicating processing requires autocatalytic cleavage. Abolishing the MC14/MECL-1 active site abrogates proteasomal trypsin-like activity without affecting other catalytic activities.\",\n      \"method\": \"Active-site mutagenesis, stable cell line expression, proteasome activity assays\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — active-site mutagenesis with defined enzymatic readout\",\n      \"pmids\": [\"10413086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"MECL-1 (PSMB10) mRNA is predominantly expressed in thymus, lymph nodes, and spleen, with a reciprocal expression pattern to its constitutive homolog MC14; tissues with high MECL-1 expression contain little MC14 and vice versa, reflected in the protein subunit composition of purified 20S proteasomes.\",\n      \"method\": \"Northern blot, 20S proteasome purification and subunit analysis from multiple tissues\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct biochemical fractionation confirming tissue-specific immunoproteasome composition\",\n      \"pmids\": [\"9174609\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Overexpression of all three inducible subunits LMP2, LMP7, and MECL-1 (PSMB10) together in triple transfectants markedly enhances MHC class I-restricted antigen presentation of an LCMV epitope; immunoproteasomes generate higher amounts of N-terminally extended peptide precursors in vitro compared to constitutive proteasomes.\",\n      \"method\": \"Triple transfection, in vitro proteasome cleavage assay, antigen presentation assay (CTL killing)\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro reconstitution of cleavage plus functional antigen presentation assay, replicated across conditions\",\n      \"pmids\": [\"10878350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Structure-based design using co-crystal structures of β2i (PSMB10) with humanized yeast proteasomes identified differences in substrate-binding channels between β2c and β2i, enabling development of selective inhibitor LU-002i (IC50 β2i: 220 nM, 45-fold selectivity over β2c). Yeast mutagenesis confirmed residues critical for subunit specificity.\",\n      \"method\": \"X-ray crystallography, activity-based protein profiling, yeast mutagenesis, chemical synthesis\",\n      \"journal\": \"Journal of medicinal chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus mutagenesis plus in vitro biochemical validation in single study\",\n      \"pmids\": [\"30657666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PSMB10 (β2i/LMP10) promotes PTEN degradation and AKT1 activation in cardiac atrial tissue, which activates TGF-β-Smad2/3 signaling (leading to fibrosis) and IKKβ-mediated ubiquitin-dependent degradation of IκBα (activating NF-κB target genes IL-1β, IL-6, NOX2, NOX4, CX43); PSMB10 KO mice are protected from Ang II-induced atrial fibrillation while AAV9-PSMB10 overexpression aggravates it.\",\n      \"method\": \"Knockout mice, AAV9 overexpression, IKKβ inhibitor treatment, Western blot for pathway components\",\n      \"journal\": \"Hypertension\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with mechanistic pathway validation and pharmacological confirmation, single lab\",\n      \"pmids\": [\"29507100\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Knockout of immunoproteasome subunit β2i (PSMB10) in DOCA/salt hypertensive mice attenuates cardiac fibrosis and inflammation, associated with inhibition of IκBα/NF-κB and TGF-β1/Smad2/3 signaling pathways.\",\n      \"method\": \"Knockout mice, echocardiography, histology, Western blot, qPCR\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with defined signaling pathway readout, single lab\",\n      \"pmids\": [\"28478040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"LMP10 (PSMB10) upregulation in retinal tissue promotes PTEN degradation and AKT/IKK signaling activation, inducing IκBα phosphorylation and NF-κB target gene activation during Ang II-induced retinopathy; LMP10 KO mice are protected and intravitreal rAAV2-LMP10 injection aggravates retinopathy.\",\n      \"method\": \"KO mice, intravitreal AAV injection, IKKβ inhibitor, Western blot, histology, ROS assays\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with gain-of-function and pharmacological corroboration, single lab\",\n      \"pmids\": [\"29499566\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LMP10 (PSMB10) deficiency in ApoE KO mice attenuates atherosclerosis by shifting macrophage polarization (increased M2/M1 ratio) and reducing NF-κB activation via decreased IκBα degradation; myeloid-specific deletion via bone marrow transplantation recapitulates this phenotype, confirming macrophage-intrinsic action.\",\n      \"method\": \"Genetic KO, bone marrow transplantation, in vitro macrophage culture with ox-LDL, flow cytometry, Western blot\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — cell-type-specific KO via bone marrow transplant plus in vitro mechanistic validation\",\n      \"pmids\": [\"33195259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LMP10 (PSMB10) deficiency attenuates Ang II-induced cardiac hypertrophy via autophagy-dependent degradation of IGF1R and gp130, reducing downstream AKT, mTOR, STAT3, and ERK1/2 phosphorylation; inhibiting autophagy with chloroquine reverses the protective effect of LMP10 knockdown.\",\n      \"method\": \"KO mice, in vitro siRNA knockdown, chloroquine autophagy inhibition, Western blot, echocardiography\",\n      \"journal\": \"Frontiers in physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological rescue experiment plus in vivo KO with defined molecular pathway\",\n      \"pmids\": [\"32581853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"β2i (PSMB10) expression is reduced in I/R myocardium; β2i KO causes excessive mitochondrial fission due to increased Parkin E3 ligase expression and consequent degradation of mitofusin 1/2 (Mfn1/2), worsening cardiac I/R injury; conversely, rAAV9-β2i overexpression is cardioprotective.\",\n      \"method\": \"KO mice, rAAV9 overexpression, Western blot for Parkin/Mfn1/2/Drp1, mitochondrial morphology analysis\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO plus gain-of-function with defined molecular mechanism (Parkin-Mfn1/2 axis), single lab\",\n      \"pmids\": [\"37501008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Adenovirus E1A protein directly interacts with immunoproteasome subunit MECL-1 (PSMB10) via its N-terminal region and conserved region 3, but binds poorly to the constitutive β2 subunit. E1A causes downregulation of MECL-1, LMP2, and LMP7 expression induced by IFN-γ, at least partly through reducing IFN-γ-stimulated STAT1 phosphorylation.\",\n      \"method\": \"Co-immunoprecipitation, cotransfection, Western blot for STAT1 phosphorylation\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct binding demonstrated by Co-IP with domain mapping, plus mechanistic downstream pathway link\",\n      \"pmids\": [\"22018786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"T cells from double-knockout mice lacking both MECL-1 (PSMB10) and LMP7 hyperproliferate in response to polyclonal mitogens (both CD4+ and CD8+), with accelerated cell cycling; single-subunit KO mice do not show this phenotype, placing both subunits jointly in a pathway that limits T cell proliferation independent of MHC class I antigen processing.\",\n      \"method\": \"Double-KO mice, in vitro proliferation assays, CFSE cell cycle analysis, flow cytometry\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean double-KO with defined cellular phenotype and genetic epistasis controls\",\n      \"pmids\": [\"16547243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"LMP7/MECL-1 double-KO splenocytes show altered cytokine mRNA expression (IFNγ, IL-4, IL-10, IL-2Rβ, GATA3, t-bet) upon PMA/ionomycin activation, while regulation of IL-2, IL-13, TNFα, and IL-2Rα by the proteasome is independent of these two subunits, indicating PSMB10 specifically regulates a subset of cytokine responses.\",\n      \"method\": \"LMP7/MECL-1 double-KO mice, qPCR cytokine profiling, lactacystin treatment\",\n      \"journal\": \"Pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with specific cytokine dissection, single lab\",\n      \"pmids\": [\"22398747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A heterozygous dominant-negative PSMB10 G201R variant markedly reduces immunoproteasome protein expression (PSMB9 and PSMB10) in patient PBMCs, EBV-B cells, and fibroblasts. CD34+ cells show impaired generation of CD3+TCRαβ+ cells in artificial thymic organoids. Single-cell RNA-seq demonstrates PSMB10 expression in cortical and medullary thymic epithelial cell subsets, indicating a role in thymic positive and negative selection of T cells.\",\n      \"method\": \"Immunoblotting, flow cytometry, artificial thymic organoid T cell development assay, single-cell RNA-seq of human thymus\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods in patient-derived cells with functional T cell development assay\",\n      \"pmids\": [\"39734035\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Genetic inactivation of PSMB10 in AML cells increases senescence, boosts SLC22A16-mediated drug endocytosis leading to chemotherapy-induced senescence via the RPL6/RPS6-MDM2-P21 pathway, impedes MHC-I protein degradation thereby restoring CTL-mediated killing, and reduces leukemia stem cell frequency 19-fold in xenograft models.\",\n      \"method\": \"siRNA/lentiviral KO, co-immunoprecipitation, Western blot, polysome profiling, quantitative proteomics, xenograft and syngeneic BMT models, in vitro CTL killing assay\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal in vitro and in vivo methods with defined mechanistic pathways, single lab\",\n      \"pmids\": [\"40462177\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"A dominant-negative PSMB10 p.G209R mutation disrupts immunoproteasome assembly and function, as confirmed by molecular modeling and proteomics; interferon-γ-treated fibroblasts from the patient show defective viral sensing and antigen presentation signatures, yet hematopoietic stem cells retain the ability to differentiate into T cells ex vivo.\",\n      \"method\": \"Molecular modeling, proteomics, transcriptomics, ex vivo T lymphopoiesis from patient HSCs\",\n      \"journal\": \"Journal of human immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple biochemical and functional methods in patient-derived cells, single case study\",\n      \"pmids\": [\"41971628\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PSMB10 (MECL-1/β2i/LMP10) is an IFN-γ-inducible catalytic beta subunit that is incorporated into the 20S immunoproteasome in obligatory co-dependence with LMP2, replacing the constitutive MC14 subunit via autocatalytic prosequence cleavage to confer trypsin-like proteolytic activity; within the immunoproteasome it shapes MHC class I antigen presentation by generating peptide precursors, while outside classical antigen processing it regulates NF-κB signaling (via PTEN/AKT/IKKβ-mediated IκBα degradation), mitochondrial dynamics (via Parkin-Mfn1/2), autophagy-dependent receptor turnover, T cell proliferation, cytokine production, and thymic T cell development, making it a broad regulator of both adaptive immunity and cardiovascular/inflammatory pathology.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll first classify each paper, then extract discoveries from KEEP papers only.\n\n**Classification:**\n\n- Papers [1]-[11] (retrieved): KEEP — all describe PSMB10/MECL-1/LMP10/β2i immunoproteasome subunit\n- Papers [12], [15], [23]-[27] (retrieved): KEEP — describe PSMB10/LMP10/MECL-1 in various contexts\n- Papers [13], [14], [16]-[19] (retrieved): KEEP — PSMB10/LMP10 functional studies\n- Paper [20] (retrieved, medaka PSMB10): KEEP — ortholog study\n- Papers [21]-[22] (retrieved, integrin β2I-domain): EXCLUDE — alias collision (\"β2I\" = integrin β2 I-domain, not PSMB10)\n- Paper [28] (retrieved, AML): KEEP — PSMB10 in leukemia\n- Papers [29]-[31] (retrieved): KEEP\n- Paper [32] (preprint): KEEP\n\n**Additional gene2pubmed papers:**\n- Papers about APOBEC3G/CEM15, GWAS, interactomes, cDNA libraries, APC/C, Emi1, cyclin A: EXCLUDE — clearly about other genes (APOBEC3G, etc.) or generic resources with no specific PSMB10 mechanism\n- PMID:8811196 (structure/functions 20S/26S proteasome): KEEP as context, but generic review\n- PMID:25056061 (schizophrenia GWAS): EXCLUDE\n- BioPlex/interactome papers: EXCLUDE (no specific PSMB10 mechanism extracted)\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1996,\n      \"finding\": \"MECL-1 (LMP10/PSMB10) was identified as the third IFN-gamma-inducible proteasome beta-type subunit. Upon IFN-gamma stimulation, LMP10 (along with LMP2 and LMP7) is incorporated into proteasomes while constitutive counterparts (LMP9, LMP17, LMP19) are displaced; MECL-1 was shown to be the product of the previously cloned MECL-1 gene and to harbor most or all catalytic sites of the proteasome.\",\n      \"method\": \"2D gel electrophoresis of IFN-gamma-treated cell lysates, Northern blot, protein fractionation of proteasome complexes\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal biochemical methods, foundational identification study replicated across subsequent work\",\n      \"pmids\": [\"8786291\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The incorporation of MECL-1 (PSMB10) into the 20S proteasome requires LMP2; conversely, LMP2 incorporation is strongly enhanced by MECL-1. MECL-1 replaces the constitutive homologous subunit Z. This obligatory co-incorporation of MECL-1 and LMP2 occurs at the level of proteasome precursor formation, indicating concerted assembly of IFN-gamma-inducible subunits encoded inside and outside the MHC.\",\n      \"method\": \"Cotransfection experiments, immunoprecipitation of 20S proteasome complexes, Western blot analysis of subunit composition\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP with cotransfection, replicated by multiple subsequent studies\",\n      \"pmids\": [\"9256419\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Mouse MECL-1 (PSMB10) and its constitutive homolog MC14 show reciprocal tissue expression: MECL-1 mRNA is highest in thymus, lymph nodes, and spleen, while MC14 predominates in tissues with low MECL-1. This reciprocal pattern mirrors that of LMP2/delta and LMP7/MB1 pairs, and the protein composition of purified 20S proteasomes from liver, thymus, and lung reflects this RNA expression.\",\n      \"method\": \"Northern blot analysis, 20S proteasome purification and subunit protein composition analysis from multiple tissues\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — proteasome purification plus RNA blots, consistent tissue-level findings\",\n      \"pmids\": [\"9174609\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The MECL-1 (PSMB10) active site is responsible for the trypsin-like activity of the proteasome. A catalytically inactive mutant MECL-1 (active-site mutation) was incorporated normally into cytosolic proteasomes, replacing the constitutive MC14 subunit, but its prosequence removal was incomplete (indicating autocatalytic processing). Absence of the MC14/MECL-1 active sites specifically abrogated trypsin-like proteolytic activity without affecting other catalytic activities, and cleavage specificity is conserved between mammalian and yeast proteasomes.\",\n      \"method\": \"Site-directed mutagenesis of catalytic residue, stable cell line generation, proteasome purification, peptidase activity assays\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — active-site mutagenesis with direct enzymatic readout, conservation shown across species\",\n      \"pmids\": [\"10413086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Overexpression of all three immunoproteasome subunits (LMP2, LMP7, MECL-1/PSMB10) in triple transfectants markedly enhanced MHC class I-restricted presentation of the LCMV NP118 epitope. In vitro, immunoproteasomes generated higher amounts of 11- and 12-mer precursor fragments containing the NP118 epitope compared to constitutive proteasomes, demonstrating that MECL-1 inclusion alters antigen processing specificity.\",\n      \"method\": \"Triple transfection of immunosubunits, T cell epitope presentation assay, in vitro proteasome digestion assay with peptide fragment analysis\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — functional antigen presentation assay combined with in vitro digestion, multiple orthogonal methods\",\n      \"pmids\": [\"10878350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"T cells from double knockout mice lacking both MECL-1 (PSMB10) and LMP7 hyperproliferate in vitro in response to polyclonal mitogens, with accelerated cell cycling in both CD4+ and CD8+ subsets. This hyperproliferation is not observed in single knockouts, and in vivo there are increased numbers of central memory CD8+ T cells, implicating immunoproteasomes in T cell proliferation control beyond MHC class I antigen processing.\",\n      \"method\": \"Double knockout mouse model, mitogen stimulation assay, flow cytometry for cell cycling and T cell subsets, in vivo phenotyping\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with defined cellular phenotype, multiple T cell subsets analyzed\",\n      \"pmids\": [\"16547243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Adenovirus E1A directly binds MECL-1 (PSMB10) through its N-terminal region and conserved region 3, while binding poorly to the constitutive β2 subunit. E1A causes downregulation of MECL-1 (and LMP2 and LMP7) expression induced by IFN-gamma, and this downregulation is mediated by reduced IFN-gamma-stimulated STAT1 phosphorylation.\",\n      \"method\": \"Co-immunoprecipitation, cotransfection, Western blot, binding domain mapping\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct binding demonstrated by Co-IP with domain mapping, single lab\",\n      \"pmids\": [\"22018786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"LMP7 and MECL-1 (PSMB10) jointly regulate cytokine expression (IFN-gamma, IL-4, IL-10, IL-2Rβ, GATA3, and t-bet) in activated splenocytes, while other cytokines (IL-2, IL-13, TNF-alpha, IL-2Rα) are regulated by the proteasome independently of LMP7/MECL-1.\",\n      \"method\": \"LMP7/MECL1-null mouse, splenocyte activation with PMA/ionomycin, quantitative RT-PCR for cytokine mRNAs, lactacystin inhibitor treatment\",\n      \"journal\": \"Pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with defined transcriptional phenotype, but single lab\",\n      \"pmids\": [\"22398747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Knockout of immunoproteasome subunit β2i (PSMB10) in DOCA/salt hypertensive mice attenuates cardiac fibrosis and inflammation. Mechanistically, β2i KO inhibits IκBα/NF-κB and TGF-β1/Smad2/3 signaling pathways, reducing expression of collagen I, collagen III, α-SMA, IL-1β, IL-6, and TNF-α.\",\n      \"method\": \"β2i knockout mouse model, DOCA/salt hypertension model, echocardiography, histological staining, qRT-PCR, Western blot\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with defined pathway inhibition and cardiac phenotype, single lab\",\n      \"pmids\": [\"28478040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PSMB10 (β2i/LMP10) promotes PTEN degradation and AKT1 activation in atrial tissue during angiotensin II stimulation, which activates IKKβ and drives ubiquitin-mediated IκBα degradation and NF-κB target gene expression (IL-1β, IL-6, NOX2, NOX4, CX43), leading to atrial fibrosis and reactive oxygen species production. PSMB10 KO mice are protected from Ang II-induced atrial fibrillation while AAV9-PSMB10 overexpression aggravates it.\",\n      \"method\": \"PSMB10 knockout mice, rAAV9-PSMB10 overexpression, Ang II infusion model, IKKβ inhibitor (IMD-0354), Western blot for pathway components, proteasome activity assay\",\n      \"journal\": \"Hypertension\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO and overexpression with pharmacological rescue, mechanistic pathway dissection\",\n      \"pmids\": [\"29507100\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"LMP10 (PSMB10) promotes PTEN degradation and activation of AKT/IKK signaling in retinal cells during Ang II stimulation, leading to IκBα phosphorylation and degradation and NF-κB target gene activation, causing hypertensive retinopathy with increased vascular permeability, ROS production, and inflammation.\",\n      \"method\": \"LMP10 knockout mice, intravitreal rAAV2-LMP10 injection, IKKβ inhibitor (IMD-0354), pathological staining, proteasome trypsin-like activity assay, Western blot\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO plus overexpression with pharmacological intervention, multiple orthogonal readouts\",\n      \"pmids\": [\"29499566\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PSMB10 interacts directly with classical swine fever virus NS3 protein (confirmed by Co-IP, GST pulldown, and confocal microscopy). PSMB10 overexpression inhibits CSFV replication and promotes ubiquitin-proteasome-dependent degradation of NS3. Additionally, PSMB10 restores MHC class I antigen presentation that CSFV had suppressed.\",\n      \"method\": \"Yeast two-hybrid screening, co-immunoprecipitation, GST pulldown, laser confocal microscopy, overexpression and knockdown of PSMB10, viral replication assay\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal binding assays (Y2H, Co-IP, pulldown, imaging) with functional validation\",\n      \"pmids\": [\"31493657\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Crystal structures of β2c- and β2i (PSMB10)-humanized yeast proteasomes with selective inhibitors LU-002c and LU-002i reveal significant differences in the substrate-binding channels of β2c and β2i that underlie subunit selectivity, enabling rational design of compounds with 40-45-fold selectivity for each subunit.\",\n      \"method\": \"X-ray crystallography of inhibitor-proteasome co-crystals, activity-based protein profiling, yeast mutagenesis, organic synthesis and biochemical screening\",\n      \"journal\": \"Journal of medicinal chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with mutagenesis and functional validation, multiple orthogonal methods\",\n      \"pmids\": [\"30657666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LMP10 (PSMB10) deletion attenuates atherosclerosis in ApoE KO mice by shifting macrophage polarization toward M2 and reducing NF-κB activation (decreased IκBα degradation). Myeloid-specific deletion via bone marrow transplantation recapitulates this phenotype. In vitro, LMP10 deletion blunts macrophage polarization and ox-LDL-induced foam cell formation.\",\n      \"method\": \"LMP10 KO mice, ApoE KO atherosclerosis model, bone marrow transplantation, flow cytometry for macrophage polarization, in vitro macrophage culture, Western blot\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cell-type specific KO via BMT, in vitro and in vivo orthogonal approaches\",\n      \"pmids\": [\"33195259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LMP10 (PSMB10) KO in Ang II-infused mice promotes autophagic degradation of IGF1R and gp130, reducing downstream phosphorylation of AKT, mTOR, STAT3, and ERK1/2, leading to attenuated cardiac hypertrophic remodeling. In vitro knockdown of LMP10 increases LC3II/I ratio (autophagy marker) and promotes IGF1R/gp130 degradation; chloroquine (autophagy inhibitor) reverses this effect.\",\n      \"method\": \"LMP10 KO mice, Ang II infusion, echocardiography, Western blot for signaling components, siRNA knockdown, autophagy inhibitor treatment\",\n      \"journal\": \"Frontiers in physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with mechanistic rescue by autophagy inhibition, single lab\",\n      \"pmids\": [\"32581853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Triple knockout of all three immunoproteasome catalytic subunits (β1i/LMP2, β2i/MECL-1/PSMB10, β5i/LMP7) impairs control of Toxoplasma gondii infection, reducing dendritic cell, monocyte, and CD8+ T cell numbers, impairing IFN-gamma/TNF/iNOS production, altering T cell differentiation, elevating apoptosis of microglia and monocytes, and diminishing STAT3 downstream signaling.\",\n      \"method\": \"Triple immunoproteasome KO mice, T. gondii infection model, flow cytometry, STAT3 signaling analysis, cytokine measurement\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with multiple cellular readouts, but triple KO cannot isolate PSMB10-specific contribution\",\n      \"pmids\": [\"33968021\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"β2i (PSMB10) KO in mice subjected to cardiac I/R injury results in excessive mitochondrial fission due to Mfn1/2 and Drp1 imbalance. Mechanistically, I/R reduces β2i expression and activity, which increases Parkin E3 ligase expression and promotes ubiquitin-dependent degradation of mitofusin 1/2 (Mfn1/2), causing mitochondrial fragmentation. Cardiac overexpression of β2i via rAAV9 ameliorates I/R injury.\",\n      \"method\": \"β2i KO mice, rAAV9-β2i overexpression, cardiac I/R model, electron microscopy for mitochondrial morphology, Western blot for Parkin/Mfn1/2/Drp1, infarct size measurement\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO plus overexpression with mechanistic pathway identified, single lab\",\n      \"pmids\": [\"37501008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A heterozygous dominant-negative PSMB10 variant (G201R) markedly reduces immunoproteasome protein expression (PSMB9 and PSMB10) in PBMCs, EBV-B cells, and fibroblasts. PSMB10 is expressed in cortical and medullary thymic epithelial cell subsets (per scRNA-seq). The mutation impairs positive selection of CD8 T cells, generation of T cell receptor diversity, and negative selection of autoreactive T cells, causing severe combined immunodeficiency and Omenn syndrome.\",\n      \"method\": \"Immunoblotting, flow cytometry, artificial thymic organoid T-cell development assay, human thymus single-cell RNA sequencing, immunophenotyping\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including scRNA-seq, functional thymic organoid assay, and protein expression analysis\",\n      \"pmids\": [\"39734035\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PSMB10 maintains stemness of chemotherapy-resistant leukemia stem cells by inhibiting senescence and cytotoxic T lymphocyte killing. Mechanistically, PSMB10 downregulation boosts SLC22A16-mediated drug endocytosis and induces chemotherapy-mediated senescence via the RPL6/RPS6-MDM2-P21 pathway. Additionally, PSMB10 promotes MHC-I protein degradation to enable immune escape from CTL killing. Genetic inactivation of PSMB10 in vivo reduces human LSC frequency 19-fold and drug-resistant mouse LSC frequency 7.6-fold.\",\n      \"method\": \"siRNA/lentivirus knockdown, co-immunoprecipitation, luciferase reporter assays, polysome profiling, quantitative proteomics, xenograft and syngeneic BMT mouse models, flow cytometry\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal mechanistic methods with in vivo validation\",\n      \"pmids\": [\"40462177\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"A dominant-negative PSMB10 p.G209R mutation disrupts immunoproteasome assembly and function, leading to defective viral sensing and antigen presentation in IFN-treated fibroblasts, causing severe T lymphopenia at birth. Molecular modeling and biochemical studies confirmed impaired immunoproteasome assembly. Despite this, the patient recovered normal naïve T cell counts and T cell receptor diversity within the first year of life.\",\n      \"method\": \"Molecular modeling, proteomics, transcriptomics, ex vivo T lymphopoiesis, immunoproteasome assembly and function assays\",\n      \"journal\": \"Journal of human immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — molecular modeling with biochemical confirmation, single patient/lab\",\n      \"pmids\": [\"41971628\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PSMB10 (β2i/MECL-1/LMP10) is an IFN-gamma-inducible catalytic beta subunit of the immunoproteasome whose incorporation requires obligatory co-assembly with LMP2, replaces the constitutive Z/MC14 subunit, provides the trypsin-like proteolytic activity of the complex, and alters antigen processing to enhance MHC class I peptide presentation; beyond antigen presentation, PSMB10 promotes NF-κB signaling through PTEN degradation and IκBα ubiquitination, regulates mitochondrial dynamics by controlling Parkin-dependent Mfn1/2 degradation, prevents autophagy-dependent clearance of pro-hypertrophic receptors (IGF1R, gp130), and maintains leukemia stem cell stemness through the RPL6/RPS6-MDM2-P21 senescence pathway and MHC-I degradation-mediated immune escape.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PSMB10 (MECL-1/β2i/LMP10) is an IFN-γ-inducible catalytic β-type subunit of the 20S immunoproteasome that replaces the constitutive subunit MC14 via autocatalytic prosequence cleavage to confer trypsin-like proteolytic activity, and whose incorporation requires obligatory co-dependence with LMP2 at the level of proteasome precursor assembly [PMID:8786291, PMID:9256419, PMID:10413086]. Within the immunoproteasome, PSMB10 generates N-terminally extended peptide precursors that enhance MHC class I-restricted antigen presentation, and in concert with LMP7, it limits T cell proliferation and regulates a specific subset of cytokine responses [PMID:10878350, PMID:16547243, PMID:22398747]. Beyond classical antigen processing, PSMB10 promotes PTEN degradation and consequent AKT/IKKβ-mediated NF-κB activation across multiple tissues, regulates mitochondrial dynamics through the Parkin–Mfn1/2 axis, and modulates autophagy-dependent receptor turnover, positioning it as a key mediator of inflammatory and cardiovascular pathology [PMID:29507100, PMID:37501008, PMID:32581853]. Dominant-negative PSMB10 mutations impair immunoproteasome assembly and disrupt thymic T cell development, establishing PSMB10 as a cause of human immunodeficiency [PMID:39734035, PMID:41971628].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Identifying PSMB10 as the third IFN-γ-inducible proteasome subunit established that the immunoproteasome contains a complete set of replacement catalytic β subunits rather than only two.\",\n      \"evidence\": \"Protein identification, Northern blot, and proteasome fractionation in IFN-γ-treated cells\",\n      \"pmids\": [\"8786291\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Catalytic specificity of MECL-1 not yet defined\", \"Mechanism of incorporation into proteasome precursors unknown\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Demonstrating obligatory co-dependence of MECL-1 and LMP2 for proteasome incorporation revealed that immunoproteasome assembly is a coordinated, not independent, process occurring at the precursor level.\",\n      \"evidence\": \"Cotransfection, proteasome immunoprecipitation, and Western blot showing reciprocal incorporation dependence\",\n      \"pmids\": [\"9256419\", \"9174609\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of co-dependence not resolved\", \"Whether LMP7 also gates MECL-1 incorporation not fully addressed\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Active-site mutagenesis established that MECL-1 provides the trypsin-like catalytic activity of the proteasome and undergoes autocatalytic prosequence cleavage for maturation, directly linking one specific peptidase activity to this subunit.\",\n      \"evidence\": \"Thr1 active-site mutant in stable cell lines with fluorogenic substrate assays\",\n      \"pmids\": [\"10413086\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural data on human β2i active site at this point\", \"In vivo peptide repertoire consequences not shown\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Triple transfection of all three inducible subunits showed that immunoproteasomes generate enhanced N-terminally extended MHC class I peptide precursors, directly connecting PSMB10 to improved antigen presentation.\",\n      \"evidence\": \"In vitro proteasome cleavage assays and CTL killing assays with LCMV epitopes\",\n      \"pmids\": [\"10878350\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Individual contribution of MECL-1 versus LMP2/LMP7 to cleavage specificity not separated\", \"In vivo antigen presentation impact not tested\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Double-KO of MECL-1 and LMP7 revealed a non-redundant, antigen-processing-independent role for immunoproteasome subunits in restraining T cell proliferation, expanding the functional scope beyond peptide generation.\",\n      \"evidence\": \"MECL-1/LMP7 double-KO mice with CFSE proliferation assays and cell cycle analysis\",\n      \"pmids\": [\"16547243\", \"22398747\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular target(s) controlling cell cycle in T cells not identified\", \"Single-subunit KO does not phenocopy, so epistasis mechanism is unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identification of adenovirus E1A as a direct MECL-1-binding protein that suppresses immunoproteasome expression established a viral immune evasion mechanism targeting PSMB10.\",\n      \"evidence\": \"Co-immunoprecipitation with domain mapping, Western blot for STAT1 phosphorylation\",\n      \"pmids\": [\"22018786\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No reciprocal pull-down or in vitro binding with purified proteins\", \"Functional consequence for viral antigen presentation not directly measured\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"A series of KO and overexpression studies in cardiovascular and inflammatory disease models demonstrated that PSMB10 promotes PTEN degradation and NF-κB activation via AKT/IKKβ, establishing an immunoproteasome-NF-κB signaling axis outside classical antigen processing.\",\n      \"evidence\": \"PSMB10 KO and AAV9 overexpression mice in Ang II, DOCA/salt, and ApoE−/− atherosclerosis models with pathway dissection by Western blot and IKKβ inhibitors\",\n      \"pmids\": [\"28478040\", \"29507100\", \"29499566\", \"33195259\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether PTEN is a direct immunoproteasome substrate or degraded indirectly is unresolved\", \"All cardiovascular studies from overlapping research groups; independent replication pending\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Co-crystal structures of β2i with humanized yeast proteasomes defined the substrate-binding channel differences from β2c, enabling rational design of the first β2i-selective inhibitor LU-002i.\",\n      \"evidence\": \"X-ray crystallography, activity-based protein profiling, yeast mutagenesis\",\n      \"pmids\": [\"30657666\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Human immunoproteasome crystal structure not yet obtained\", \"In vivo pharmacology of LU-002i not reported\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"PSMB10 deficiency was shown to promote autophagy-dependent degradation of growth factor receptors IGF1R and gp130, revealing a previously unknown link between immunoproteasome activity and receptor turnover via autophagy.\",\n      \"evidence\": \"KO mice and siRNA knockdown with chloroquine rescue experiments and echocardiography\",\n      \"pmids\": [\"32581853\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which PSMB10 loss activates selective autophagy not defined\", \"Whether this receptor turnover occurs in non-cardiac cells is unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"PSMB10 was linked to mitochondrial dynamics through regulation of Parkin levels and consequent Mfn1/2 degradation, showing that loss of β2i causes excessive mitochondrial fission during cardiac ischemia/reperfusion.\",\n      \"evidence\": \"KO mice and rAAV9 overexpression with mitochondrial morphology analysis and Western blot for Parkin/Mfn1/2\",\n      \"pmids\": [\"37501008\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether Parkin is a direct proteolytic substrate of the immunoproteasome is untested\", \"Mechanism applies to cardiac tissue; generality unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"A dominant-negative PSMB10 variant (G201R) was identified as causing human immunodeficiency with impaired T cell development, establishing PSMB10 as a disease gene for proteasome-associated autoinflammatory syndrome and linking immunoproteasome function to thymic selection.\",\n      \"evidence\": \"Patient-derived cells, immunoblotting, artificial thymic organoid assay, scRNA-seq of human thymus\",\n      \"pmids\": [\"39734035\", \"41971628\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Only single/few patients described; phenotypic spectrum not fully delineated\", \"Whether thymic epithelial cell-intrinsic or T cell-intrinsic defect predominates is unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"PSMB10 inactivation in AML cells was shown to restore MHC-I surface expression by impeding its degradation and to promote chemosensitivity via senescence through the RPL6/RPS6-MDM2-P21 axis, identifying PSMB10 as a therapeutic target in leukemia.\",\n      \"evidence\": \"siRNA/lentiviral KO, quantitative proteomics, polysome profiling, xenograft models, in vitro CTL killing\",\n      \"pmids\": [\"40462177\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single study; awaits independent validation in other AML cohorts\", \"Direct mechanism linking PSMB10 to ribosomal protein–MDM2 interaction not fully elucidated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: whether PTEN and Parkin are direct proteolytic substrates of the PSMB10-containing immunoproteasome; the structural basis of human immunoproteasome assembly requiring PSMB10–LMP2 co-dependence; and how immunoproteasome activity controls selective autophagy and T cell homeostasis at the molecular level.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No in vitro reconstitution with purified human immunoproteasomes for proposed non-canonical substrates\", \"Full human β2i immunoproteasome structure not reported\", \"Molecular mechanism linking immunoproteasome to autophagy pathway undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [2, 5]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2, 4, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2, 0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4, 13, 15, 16]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 2, 4, 5]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 7, 8, 9, 10]}\n    ],\n    \"complexes\": [\n      \"20S immunoproteasome\"\n    ],\n    \"partners\": [\n      \"PSMB9\",\n      \"PSMB8\",\n      \"PTEN\",\n      \"NFKBIA\",\n      \"PRKN\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"PSMB10 (β2i/MECL-1/LMP10) is an IFN-γ-inducible catalytic subunit of the immunoproteasome that replaces the constitutive β2 (Z/MC14) subunit, provides the trypsin-like proteolytic activity of the 20S complex, and requires obligatory co-incorporation with LMP2 during proteasome precursor assembly [PMID:8786291, PMID:9256419, PMID:10413086]. Incorporation of PSMB10 together with LMP2 and LMP7 alters cleavage specificity to enhance generation of MHC class I-restricted peptide epitopes, and dominant-negative PSMB10 mutations that disrupt immunoproteasome assembly cause severe combined immunodeficiency and Omenn syndrome through impaired thymic T-cell selection [PMID:10878350, PMID:39734035]. Beyond antigen processing, PSMB10 promotes NF-κB signaling by driving PTEN degradation and IκBα turnover in cardiovascular and retinal tissues, regulates mitochondrial dynamics by controlling Parkin-dependent Mfn1/2 degradation during ischemia-reperfusion injury, and maintains leukemia stem cell stemness through MHC-I degradation-mediated immune evasion and suppression of RPL6/RPS6–MDM2–P21 senescence [PMID:29507100, PMID:37501008, PMID:40462177]. Loss of PSMB10 also shifts macrophage polarization toward an M2 phenotype and attenuates atherosclerosis, while combined loss with LMP7 deregulates T-cell proliferation and cytokine expression [PMID:33195259, PMID:16547243].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"The identity of the third IFN-γ-inducible proteasome catalytic subunit was unknown; identification of MECL-1/PSMB10 as an exchangeable β-type subunit established the full complement of immunoproteasome catalytic subunits.\",\n      \"evidence\": \"2D gel electrophoresis and Northern blot of IFN-γ-treated cell lysates with proteasome fractionation\",\n      \"pmids\": [\"8786291\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Catalytic specificity of the MECL-1 active site was not yet defined\", \"Tissue-level expression pattern not resolved\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"How immunoproteasome subunits encoded at different genomic loci are coordinately assembled was unclear; demonstration that MECL-1 incorporation requires LMP2 co-incorporation during precursor formation established the obligatory cooperative assembly rule and identified the constitutive β2 subunit Z as the displaced counterpart.\",\n      \"evidence\": \"Cotransfection, immunoprecipitation of 20S proteasome complexes, tissue-level RNA and protein analysis across mouse organs\",\n      \"pmids\": [\"9256419\", \"9174609\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the LMP2-MECL-1 cooperative assembly not resolved\", \"Whether assembly cooperativity is absolute or quantitative in all cell types\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"The specific catalytic activity contributed by the β2i active site was undefined; active-site mutagenesis showed that MECL-1 provides the trypsin-like activity of the proteasome, with conservation from yeast to mammals.\",\n      \"evidence\": \"Site-directed mutagenesis of catalytic Thr residue, stable cell lines, peptidase activity assays on purified proteasomes\",\n      \"pmids\": [\"10413086\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo substrate repertoire of the trypsin-like site not identified\", \"Structural basis for cleavage preference not yet available\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Whether immunoproteasome incorporation actually alters antigen processing output was unresolved; triple transfection of LMP2/LMP7/MECL-1 demonstrated enhanced MHC class I epitope generation both in cellulo and in vitro, directly linking immunoproteasome composition to antigen presentation quality.\",\n      \"evidence\": \"Triple transfection of immunosubunits, T-cell epitope presentation assay, in vitro proteasome digestion with fragment analysis\",\n      \"pmids\": [\"10878350\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Individual contribution of MECL-1 versus LMP2/LMP7 to altered cleavage not separated\", \"Epitope repertoire breadth analysis limited to one viral epitope\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Whether immunoproteasome subunits have functions beyond antigen presentation was uncertain; MECL-1/LMP7 double-KO mice revealed cell-intrinsic T-cell hyperproliferation and altered memory differentiation, establishing a non-antigen-processing role in T-cell homeostasis.\",\n      \"evidence\": \"Double KO mouse model, mitogen stimulation, flow cytometry of T-cell subsets\",\n      \"pmids\": [\"16547243\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Individual contribution of MECL-1 versus LMP7 not resolved\", \"Molecular target of proliferation control not identified\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"How adenovirus evades immunoproteasome-mediated antigen presentation was unknown; E1A was shown to directly bind MECL-1 and downregulate all three immunosubunits by suppressing STAT1 phosphorylation, revealing a viral immune evasion mechanism targeting PSMB10.\",\n      \"evidence\": \"Co-immunoprecipitation, cotransfection, binding domain mapping\",\n      \"pmids\": [\"22018786\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether E1A-MECL-1 interaction is direct (no in vitro reconstitution)\", \"Functional consequence for viral immune evasion in vivo not tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"The signaling mechanism by which PSMB10 promotes inflammation in cardiovascular tissue was unknown; KO and overexpression studies in atrial and retinal models established that PSMB10 drives PTEN degradation, activating the AKT–IKKβ–NF-κB axis to promote fibrosis, ROS, and inflammation.\",\n      \"evidence\": \"PSMB10 KO mice, rAAV9 overexpression, Ang II infusion, IKKβ inhibitor rescue, Western blot pathway analysis in cardiac and retinal tissues\",\n      \"pmids\": [\"29507100\", \"29499566\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct ubiquitination mechanism for PTEN by immunoproteasome not shown\", \"Whether PTEN is a direct substrate or degraded indirectly through other E3 ligases\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Structural determinants of β2i versus β2c substrate-binding channel selectivity were undefined; co-crystal structures of humanized yeast proteasomes with selective inhibitors revealed specific channel differences enabling rational design of β2i-selective compounds.\",\n      \"evidence\": \"X-ray crystallography of inhibitor-proteasome co-crystals, activity-based protein profiling, yeast mutagenesis\",\n      \"pmids\": [\"30657666\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structure of fully human immunoproteasome at this site\", \"In vivo pharmacology of selective β2i inhibitors not validated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"How PSMB10 influences cardiac hypertrophy and macrophage biology was not understood; KO studies demonstrated that PSMB10 loss promotes autophagic degradation of IGF1R/gp130 attenuating hypertrophy, and shifts macrophage polarization toward M2 to reduce atherosclerosis through decreased NF-κB activation.\",\n      \"evidence\": \"LMP10 KO mice with Ang II or ApoE-KO atherosclerosis models, bone marrow transplantation, autophagy inhibitor rescue, flow cytometry\",\n      \"pmids\": [\"32581853\", \"33195259\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking immunoproteasome to autophagy regulation not fully delineated\", \"Whether macrophage polarization shift is cell-autonomous confirmed only by BMT, not conditional KO\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"How PSMB10 intersects with mitochondrial quality control was unknown; ischemia-reperfusion studies showed that PSMB10 loss increases Parkin expression, accelerating ubiquitin-dependent Mfn1/2 degradation and causing excessive mitochondrial fission.\",\n      \"evidence\": \"β2i KO mice, rAAV9 overexpression, cardiac I/R model, electron microscopy, Western blot for Parkin/Mfn1/2/Drp1\",\n      \"pmids\": [\"37501008\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct mechanism by which immunoproteasome regulates Parkin expression not shown\", \"Single lab finding awaiting independent confirmation\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Whether PSMB10 mutations cause human immunodeficiency was unresolved; a dominant-negative G201R variant was shown to impair immunoproteasome assembly, disrupt thymic T-cell selection, and cause severe combined immunodeficiency with Omenn syndrome.\",\n      \"evidence\": \"Immunoblotting, flow cytometry, artificial thymic organoid assay, human thymus scRNA-seq, immunophenotyping\",\n      \"pmids\": [\"39734035\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of G201R dominant-negative effect not determined at atomic resolution\", \"Whether other PSMB10 variants cause milder immunodeficiency phenotypes\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"The role of PSMB10 in leukemia stem cell maintenance was unknown; PSMB10 was found to suppress senescence through the RPL6/RPS6–MDM2–P21 pathway and promote immune escape via MHC-I degradation, maintaining chemotherapy-resistant LSC stemness.\",\n      \"evidence\": \"siRNA/lentivirus knockdown, co-IP, polysome profiling, quantitative proteomics, xenograft and syngeneic mouse models\",\n      \"pmids\": [\"40462177\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PSMB10 directly degrades MHC-I or acts through intermediate substrates not resolved\", \"Therapeutic window for PSMB10 targeting in AML patients not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the full in vivo substrate repertoire of the β2i trypsin-like activity, the direct mechanism linking immunoproteasome activity to autophagy regulation and Parkin expression, and whether selective β2i inhibitors can be exploited therapeutically in cancer or autoimmunity without compromising infection defense.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No comprehensive substrate identification by proteomics for β2i-specific cleavage events\", \"Mechanism of PSMB10-dependent autophagy regulation remains indirect\", \"Therapeutic index of β2i-selective inhibition in immune-competent organisms unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 3, 4, 9, 10, 11, 12, 18]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [3, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4, 5, 7, 11, 15, 17, 18]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 3, 12]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [8, 9, 10, 13, 14]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [9, 10, 13, 16, 18]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [14]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [18]}\n    ],\n    \"complexes\": [\n      \"20S immunoproteasome\",\n      \"26S immunoproteasome\"\n    ],\n    \"partners\": [\n      \"PSMB9\",\n      \"PSMB8\",\n      \"PTEN\",\n      \"PRKN\",\n      \"MFN1\",\n      \"MFN2\",\n      \"RPL6\",\n      \"RPS6\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}