{"gene":"PSMB10","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":1997,"finding":"MECL-1 (PSMB10) incorporation into the 20S proteasome is directly dependent on LMP2 expression, and conversely, LMP2 incorporation is strongly enhanced by MECL-1 expression. MECL-1 replaces the constitutive subunit Z upon incorporation. This obligatory co-incorporation occurs at the level of proteasome precursor formation.","method":"Cotransfection experiments, immunoprecipitation of proteasome complexes, analysis of precursor assembly","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal dependency demonstrated by cotransfection and proteasome complex analysis, replicated in same study with multiple conditions and confirmed by precursor formation analysis","pmids":["9256419"],"is_preprint":false},{"year":1996,"finding":"MECL-1 (LMP10/PSMB10) is the third IFN-gamma-inducible proteasome beta subunit; its transcription is increased by IFN-gamma, and it is incorporated into proteasomes while reducing incorporation of constitutive subunits (LMP-9, LMP-17, LMP-19). Together with LMP2 and LMP7, it constitutes the catalytic sites of the immunoproteasome.","method":"2D gel electrophoresis of proteasome-associated proteins, Northern blot analysis of IFN-gamma-treated cells","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 2 / Strong — biochemical identification of protein incorporation and transcriptional regulation by IFN-gamma, replicated across multiple studies","pmids":["8786291"],"is_preprint":false},{"year":1997,"finding":"MECL-1 (PSMB10) mRNA is predominantly expressed in thymus, lymph nodes, and spleen (lymphoid tissues), with reciprocal expression to its constitutive counterpart MC14 — tissues with high MECL-1 have low MC14 and vice versa. This reciprocal pattern was reflected in the subunit protein composition of purified 20S proteasomes from liver, thymus, and lung.","method":"Northern blot analysis of mouse tissues, purification and analysis of 20S proteasomes from liver, thymus, and lung","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — tissue expression and proteasome protein composition confirmed by two orthogonal methods (Northern blot + proteasome purification), single lab","pmids":["9174609"],"is_preprint":false},{"year":1999,"finding":"MECL-1 (PSMB10) is autocatalytically processed: a catalytically inactive mutant MECL-1 was incorporated into proteasomes but showed incomplete prosequence removal. The MC14/MECL-1 active sites are specifically responsible for proteasomal trypsin-like activity, with no effect on other catalytic activities upon their loss.","method":"Mutagenesis of the active site, stable cell line expression, functional proteasome activity assays","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 1 / Moderate — active-site mutagenesis combined with functional activity assays, direct demonstration of autocatalytic processing and trypsin-like activity assignment","pmids":["10413086"],"is_preprint":false},{"year":2000,"finding":"Overexpression of all three inducible subunits (LMP2, LMP7, MECL-1) together in triple transfectants markedly enhanced MHC class I 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.","method":"Triple transfection to form immunoproteasomes, in vitro proteasome degradation assays, MHC class I antigen presentation assays","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro reconstitution of immunoproteasome activity combined with cell-based antigen presentation assay, two orthogonal methods","pmids":["10878350"],"is_preprint":false},{"year":2006,"finding":"T cells lacking both MECL-1 (PSMB10) and LMP7 (but not cells lacking only one subunit) hyperproliferate in response to polyclonal mitogens, with accelerated cell cycling in both CD4+ and CD8+ T cells. This demonstrates an immunoproteasome-specific role in T cell proliferation independent of MHC class I antigen processing.","method":"Double knockout mouse model, in vitro mitogen stimulation, cell proliferation and cell cycle analysis, flow cytometry","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with defined cellular phenotype, epistasis analysis showing the effect requires loss of both subunits, single lab","pmids":["16547243"],"is_preprint":false},{"year":2011,"finding":"Adenovirus E1A directly interacts with the immunoproteasome subunit MECL-1 (PSMB10), but binds poorly to the constitutive beta2 subunit it replaces. Binding sites on E1A for MECL-1 map to the N-terminal region and conserved region 3. E1A causes downregulation of MECL-1 expression (as well as LMP2 and LMP7) induced by IFN-gamma, acting via reduction of IFN-gamma-stimulated STAT1 phosphorylation.","method":"Co-immunoprecipitation, binding domain mapping, Western blot analysis of expression levels, STAT1 phosphorylation assays","journal":"Virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding confirmed by Co-IP with domain mapping, mechanism via STAT1 supported by western blot, single lab","pmids":["22018786"],"is_preprint":false},{"year":2012,"finding":"LMP7 and MECL-1 (PSMB10) together regulate cytokine expression including IFN-gamma, IL-4, IL-10, IL-2Rb, GATA3, and t-bet in activated splenocytes, while regulation of IL-2, IL-13, TNF-alpha, and IL-2Ra by the proteasome occurs independently of these subunits.","method":"LMP7/MECL1 double-knockout mouse splenocytes, PMA/ionomycin stimulation, quantitative RT-PCR for cytokine mRNA","journal":"Pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean KO with specific cytokine phenotype, but single method (mRNA quantification) and single lab","pmids":["22398747"],"is_preprint":false},{"year":2018,"finding":"PSMB10 (LMP10/beta2i) promotes Ang II-induced atrial fibrillation by degrading PTEN and activating AKT1, which activates TGF-beta-Smad2/3 (leading to cardiac fibrosis) and IKKbeta-mediated ubiquitin-dependent IkBa degradation (leading to NF-kB activation and upregulation of IL-1b, IL-6, NOX2, NOX4, and CX43). PSMB10 trypsin-like activity was increased in atrial tissue and serum.","method":"PSMB10 knockout mice and rAAV9-PSMB10 overexpression mice, Ang II infusion model, IKKb inhibitor treatment, Western blot for pathway components, reactive oxygen species measurement, histological analysis","journal":"Hypertension (Dallas, Tex. : 1979)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO and overexpression with defined molecular pathway, multiple pathway components analyzed, single lab","pmids":["29507100"],"is_preprint":false},{"year":2018,"finding":"LMP10 (PSMB10) upregulation in retina promotes PTEN degradation and activation of AKT/IKK signaling, leading to IkBa phosphorylation and degradation and NF-kB target gene activation in Ang II-induced retinopathy.","method":"LMP10 KO mice, rAAV2-LMP10 intravitreal injection, IKKb inhibitor treatment, Western blot for signaling pathway components, pathological staining","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO and overexpression with defined signaling pathway, consistent with parallel AF study from same lab","pmids":["29499566"],"is_preprint":false},{"year":2017,"finding":"Beta2i (PSMB10) knockout ameliorates DOCA/salt-induced cardiac fibrosis and inflammation by inhibiting IkBa/NF-kB and TGF-beta1/Smad2/3 signaling pathways.","method":"Beta2i knockout mice, DOCA/salt hypertension model, echocardiography, histological staining, Western blot, qRT-PCR","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean KO with defined pathway, but single lab, primarily KO phenotype without mechanistic dissection of direct vs indirect effects","pmids":["28478040"],"is_preprint":false},{"year":2019,"finding":"PSMB10 directly interacts with CSFV NS3 protein and degrades it through the ubiquitin-proteasome system, inhibiting viral replication. PSMB10 also restores MHC class I antigen presentation function suppressed by CSFV.","method":"Yeast two-hybrid screening, co-immunoprecipitation, GST pulldown, laser confocal microscopy, overexpression/knockdown experiments, viral replication assays","journal":"Virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — interaction confirmed by three orthogonal methods (Y2H, Co-IP, GST pulldown), functional consequence demonstrated, single lab","pmids":["31493657"],"is_preprint":false},{"year":2019,"finding":"Crystal structures of beta2i (PSMB10/MECL-1)-humanized yeast proteasomes with selective inhibitors revealed significant structural differences in the S1 substrate-binding pocket between beta2c and beta2i subunits, enabling rational design of selective inhibitors (LU-002i with IC50 220 nM for beta2i, 45-fold selectivity over beta2c).","method":"X-ray crystallography (co-crystal structures), organic synthesis, activity-based protein profiling, yeast mutagenesis, enzymatic IC50 measurements","journal":"Journal of medicinal chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures with functional validation by mutagenesis and activity-based profiling, multiple orthogonal methods","pmids":["30657666"],"is_preprint":false},{"year":2020,"finding":"LMP10 (PSMB10) knockout attenuates Ang II-induced cardiac hypertrophic remodeling via autophagy-dependent degradation of IGF1R and gp130, thereby reducing AKT/mTOR/STAT3/ERK1/2 signaling. In vitro, LMP10 knockdown activated autophagy and increased degradation of IGF1R and gp130; inhibiting autophagy with chloroquine reversed the protective effect.","method":"LMP10 KO mice, Ang II infusion, in vitro cardiomyocyte LMP10 knockdown, chloroquine autophagy inhibition, LC3II/I ratio measurement, Western blot for pathway components","journal":"Frontiers in physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO plus in vitro rescue experiment with autophagy inhibitor, multiple pathway components, single lab","pmids":["32581853"],"is_preprint":false},{"year":2020,"finding":"Myeloid-specific LMP10 deficiency (via bone marrow transplantation) attenuated atherosclerosis and reduced macrophage polarization toward M1 phenotype by decreasing IkBa degradation and NF-kB activation, demonstrating a macrophage-intrinsic role for PSMB10 in NF-kB-mediated inflammation.","method":"LMP10 KO mice, ApoE KO atherosclerosis model, bone marrow transplantation for myeloid-specific deletion, in vitro macrophage ox-LDL stimulation, Western blot, flow cytometry","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — myeloid-specific KO by bone marrow transplantation with in vitro confirmation, single lab","pmids":["33195259"],"is_preprint":false},{"year":2023,"finding":"Beta2i (PSMB10) expression in cardiomyocytes suppresses the E3 ubiquitin ligase Parkin, thereby preventing degradation of mitofusin 1/2 (Mfn1/2) and maintaining mitochondrial fusion. Loss of beta2i increases Parkin expression, promotes Mfn1/2 degradation, and causes excessive mitochondrial fission leading to enhanced I/R injury.","method":"Beta2i KO mice, rAAV9-beta2i overexpression, cardiac I/R model, Western blot for Parkin/Mfn1/Mfn2/Drp1, mitochondrial morphology analysis, cardiac function assessment","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO and overexpression with defined molecular mechanism (Parkin-Mfn1/2 pathway), single lab","pmids":["37501008"],"is_preprint":false},{"year":2024,"finding":"A heterozygous PSMB10 G201R variant acts in a dominant-negative fashion to markedly reduce immunoproteasome protein expression (PSMB9 and PSMB10) in PBMCs, EBV-transformed B cells, and fibroblasts, leading to impaired positive selection of CD8 T cells, impaired generation of diverse T cell repertoire, and impaired negative selection of autoreactive T cells. PSMB10 is expressed in cortical and medullary thymic epithelial cells (confirmed by single-cell RNA sequencing of human thymus).","method":"Patient immunophenotyping, flow cytometry, immunoblotting, T-cell development in artificial thymic organoids, single-cell RNA sequencing of human thymus","journal":"The Journal of allergy and clinical immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human genetic variant with functional studies in patient-derived cells and ex vivo thymic organoids, multiple orthogonal methods, single lab","pmids":["39734035"],"is_preprint":false},{"year":2025,"finding":"De novo dominant-negative PSMB10 variants (p.Asp205Ala and p.Ser208Phe) show poor integration into the proteasome complex and exert a dominant-negative effect on the PSMB9 subunit, leading to combined immune deficiency and liver disease.","method":"Whole exome sequencing, protein expression analysis of proteasome complex assembly, clinical immunophenotyping","journal":"Journal of human immunity","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — proteasome complex assembly analysis in patient cells, single lab, limited mechanistic detail in abstract","pmids":["42170594"],"is_preprint":false},{"year":2025,"finding":"A de novo dominant-negative PSMB10 p.G209R mutation impairs immunoproteasome assembly and function (confirmed by molecular modeling and biochemical studies), leading to defective viral sensing and antigen presentation signatures in IFN-treated fibroblasts.","method":"Molecular modeling, proteomics, transcriptomics, biochemical proteasome assembly assays, ex vivo T lymphopoiesis, Western blot","journal":"Journal of human immunity","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — molecular modeling plus biochemical confirmation with functional consequences in patient fibroblasts, multiple orthogonal methods, single lab","pmids":["41971628"],"is_preprint":false},{"year":2025,"finding":"PSMB10 knockdown in AML cells boosts SLC22A16-mediated drug endocytosis and induces chemotherapy drug-mediated senescence through the RPL6/RPS6-MDM2-P21 pathway, while also preventing MHC-I protein degradation and thereby reducing escape from cytotoxic T lymphocyte killing.","method":"siRNA knockdown, lentivirus transduction, co-immunoprecipitation, luciferase reporter assays, polysome profiling, quantitative proteomics, xenograft and syngeneic bone marrow transplantation mouse models, flow cytometry","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (proteomics, Co-IP, in vivo models), mechanistic pathway defined, single lab","pmids":["40462177"],"is_preprint":false}],"current_model":"PSMB10 (MECL-1/LMP10/beta2i) is an IFN-gamma-inducible catalytic beta subunit of the immunoproteasome that replaces the constitutive MC14/Z subunit and is obligatorily co-incorporated with LMP2 during proteasome precursor assembly; its autocatalytically processed active site confers the trypsin-like proteolytic activity of the immunoproteasome, enabling enhanced MHC class I antigen presentation. Beyond antigen processing, PSMB10 regulates NF-kB signaling (by controlling IkBa degradation), mitochondrial fusion (by suppressing Parkin-mediated Mfn1/2 degradation), T cell proliferation, and cytokine production, and dominant-negative mutations in PSMB10 disrupt immunoproteasome assembly causing severe combined immunodeficiency through impaired thymic selection."},"narrative":{"mechanistic_narrative":"PSMB10 (MECL-1/LMP10/beta2i) is an IFN-gamma-inducible catalytic beta subunit of the immunoproteasome that substitutes for the constitutive subunit Z/MC14 and confers the trypsin-like proteolytic activity of the assembled complex [PMID:8786291, PMID:10413086]. Its incorporation into 20S proteasome precursors is reciprocally coupled to LMP2, such that each subunit's assembly depends on co-expression of the other [PMID:9256419], and PSMB10 itself is autocatalytically processed during maturation [PMID:10413086]. Crystallographic analysis localizes its catalytic specificity to a distinct S1 substrate-binding pocket that differs from the constitutive beta2 subunit [PMID:30657666]. Functionally, the immunoproteasome containing PSMB10 enhances generation of MHC class I antigen precursors and antigen presentation [PMID:10878350], and PSMB10 is preferentially expressed in lymphoid tissues including thymic epithelium [PMID:9174609, PMID:39734035]. Beyond antigen processing, PSMB10 governs T cell proliferation and cytokine production together with LMP7 [PMID:16547243, PMID:22398747], and shapes inflammatory and fibrotic signaling by promoting IkBa/NF-kB activation, PTEN-AKT signaling, and TGF-beta-Smad2/3 output in cardiovascular and retinal disease models [PMID:29507100, PMID:29499566, PMID:28478040, PMID:33195259]. It additionally regulates mitochondrial fusion by suppressing Parkin-mediated degradation of mitofusins [PMID:37501008] and modulates autophagy-dependent receptor turnover [PMID:32581853]. Dominant-negative PSMB10 variants that disrupt immunoproteasome assembly and the partner subunit PSMB9 cause combined immunodeficiency through impaired thymic T cell selection [PMID:39734035, PMID:42170594, PMID:41971628].","teleology":[{"year":1996,"claim":"Establishing that PSMB10 is the third IFN-gamma-inducible catalytic subunit defined the molecular composition of the immunoproteasome and placed PSMB10 at its catalytic core alongside LMP2 and LMP7.","evidence":"2D gel electrophoresis of proteasome subunits and Northern blot of IFN-gamma-treated cells","pmids":["8786291"],"confidence":"High","gaps":["Did not resolve assembly order or interdependence with other inducible subunits","Catalytic activity contribution not yet assigned"]},{"year":1997,"claim":"Demonstrating reciprocal co-incorporation dependency between MECL-1 and LMP2 at the precursor stage revealed that immunoproteasome assembly is a cooperative, ordered process rather than independent subunit swapping, and that PSMB10 replaces the constitutive Z subunit.","evidence":"Cotransfection and immunoprecipitation of proteasome complexes with precursor assembly analysis","pmids":["9256419"],"confidence":"High","gaps":["Structural basis of the dependency not defined","Did not address how LMP7 fits into the assembly hierarchy"]},{"year":1997,"claim":"Mapping reciprocal expression of MECL-1 versus constitutive MC14 across tissues established that immunoproteasome content is set at the tissue level, concentrating PSMB10 function in lymphoid organs.","evidence":"Northern blot of mouse tissues and purification of 20S proteasomes from liver, thymus, and lung","pmids":["9174609"],"confidence":"Medium","gaps":["Cell-type-resolved expression within tissues not determined","Functional consequence of tissue-specific composition not tested"]},{"year":1999,"claim":"Active-site mutagenesis showing autocatalytic processing and assigning trypsin-like activity to the MC14/MECL-1 site defined the specific proteolytic contribution of PSMB10 to the proteasome.","evidence":"Active-site mutagenesis with stable cell lines and proteasome activity assays","pmids":["10413086"],"confidence":"High","gaps":["Substrate repertoire of trypsin-like activity not enumerated","Catalytically inactive mutant still incorporated, leaving role of catalysis in assembly unresolved"]},{"year":2000,"claim":"Reconstituting full immunoproteasomes and showing enhanced epitope precursor generation connected PSMB10-containing complexes mechanistically to improved MHC class I antigen presentation.","evidence":"Triple transfection with in vitro degradation assays and cell-based antigen presentation","pmids":["10878350"],"confidence":"High","gaps":["PSMB10-specific contribution not separable from LMP2/LMP7 in the triple transfectant","Generality across diverse epitopes not established"]},{"year":2006,"claim":"Double-knockout T cell hyperproliferation revealed an immunoproteasome function in controlling T cell cycling that is independent of antigen processing, requiring combined loss of MECL-1 and LMP7.","evidence":"LMP7/MECL-1 double-knockout mice with mitogen stimulation and cell cycle analysis","pmids":["16547243"],"confidence":"Medium","gaps":["Molecular substrate controlling proliferation not identified","Single-subunit contribution masked by epistasis"]},{"year":2012,"claim":"Defining a specific subset of cytokines regulated by LMP7/MECL-1 distinguished immunoproteasome-dependent from proteasome-general control of T cell effector programs.","evidence":"Double-knockout splenocytes with PMA/ionomycin stimulation and qRT-PCR","pmids":["22398747"],"confidence":"Medium","gaps":["mRNA-only readout without protein-level or mechanistic dissection","Direct substrates linking PSMB10 to GATA3/t-bet not identified"]},{"year":2011,"claim":"Identifying direct E1A binding to MECL-1 and IFN-gamma-induced downregulation via STAT1 revealed that viruses target PSMB10 directly to suppress immunoproteasome formation.","evidence":"Co-IP with binding domain mapping and STAT1 phosphorylation assays","pmids":["22018786"],"confidence":"Medium","gaps":["Functional consequence of E1A-MECL-1 binding for antigen presentation not quantified","Single lab, single viral protein"]},{"year":2019,"claim":"Co-crystal structures of beta2i-humanized proteasomes resolved the S1 pocket differences between beta2i and beta2c, providing the structural basis for the trypsin-like specificity and selective inhibitor design.","evidence":"X-ray crystallography with activity-based profiling, yeast mutagenesis, and IC50 measurement of selective inhibitor LU-002i","pmids":["30657666"],"confidence":"High","gaps":["Human full-length immunoproteasome structure with native beta2i not solved","In vivo selectivity of inhibitors not addressed here"]},{"year":2019,"claim":"Demonstrating direct PSMB10 interaction with and degradation of CSFV NS3 extended PSMB10 function to direct antiviral restriction beyond antigen processing.","evidence":"Yeast two-hybrid, Co-IP, GST pulldown, confocal microscopy, and viral replication assays","pmids":["31493657"],"confidence":"Medium","gaps":["Whether degradation requires immunoproteasome assembly versus free PSMB10 not resolved","Single virus, single lab"]},{"year":2018,"claim":"Loss- and gain-of-function studies in hypertension models defined a PSMB10-driven PTEN degradation/AKT-IKK-NF-kB and TGF-beta-Smad axis driving fibrosis and inflammation in cardiac and retinal tissue.","evidence":"PSMB10 KO and rAAV overexpression mice in Ang II and DOCA/salt models with IKKb inhibitor and pathway Western blots","pmids":["29507100","29499566","28478040"],"confidence":"Medium","gaps":["Direct proteolytic versus indirect regulation of PTEN/IkBa not biochemically separated","All from related model systems and single lab"]},{"year":2020,"claim":"Tissue- and cell-specific studies extended PSMB10's NF-kB and degradation roles to autophagy-dependent receptor turnover in hypertrophy and to macrophage-intrinsic M1 polarization in atherosclerosis.","evidence":"LMP10 KO mice with in vitro knockdown, chloroquine autophagy inhibition, and myeloid-specific deletion by bone marrow transplantation","pmids":["32581853","33195259"],"confidence":"Medium","gaps":["Mechanism by which PSMB10 represses autophagy not defined","Direct substrates (IGF1R, gp130) versus indirect effects not biochemically established"]},{"year":2023,"claim":"Linking beta2i to suppression of Parkin and preservation of mitofusins revealed a role in maintaining mitochondrial fusion and protecting against ischemia-reperfusion injury.","evidence":"Beta2i KO and rAAV overexpression mice in cardiac I/R with mitochondrial morphology and Parkin/Mfn1/2/Drp1 Western blots","pmids":["37501008"],"confidence":"Medium","gaps":["Whether PSMB10 controls Parkin directly through proteolysis not shown","Single lab"]},{"year":2024,"claim":"Identifying a dominant-negative PSMB10 variant that collapses immunoproteasome expression and disrupts thymic T cell selection established PSMB10 as a cause of human immunodeficiency and confirmed its thymic epithelial expression.","evidence":"Patient immunophenotyping, immunoblotting, artificial thymic organoids, and single-cell RNA sequencing of human thymus","pmids":["39734035"],"confidence":"Medium","gaps":["Structural mechanism of dominant-negative interference not fully resolved","Single patient/variant"]},{"year":2025,"claim":"Additional de novo dominant-negative variants showing poor proteasome integration and interference with PSMB9 consolidated PSMB10 deficiency as a combined immune deficiency caused by failed immunoproteasome assembly.","evidence":"Whole exome sequencing, proteasome assembly assays, molecular modeling, and patient-cell functional studies","pmids":["42170594","41971628"],"confidence":"Medium","gaps":["Quantitative structural basis of dominant-negative effect on PSMB9 not fully defined","Liver disease mechanism unexplained"]},{"year":2025,"claim":"Demonstrating that PSMB10 knockdown enhances drug-induced senescence and limits MHC-I degradation in AML positioned PSMB10 as a modulator of chemosensitivity and immune escape in cancer.","evidence":"siRNA/lentiviral knockdown, Co-IP, polysome profiling, proteomics, and xenograft/syngeneic mouse models","pmids":["40462177"],"confidence":"Medium","gaps":["Direct PSMB10 substrates in the RPL6/RPS6-MDM2-P21 axis not mapped","Single lab"]},{"year":null,"claim":"It remains unresolved which of PSMB10's non-antigen-processing roles (NF-kB, PTEN/AKT, Parkin, autophagy) reflect direct proteolytic substrates of its trypsin-like site versus indirect consequences of altered proteasome composition.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No direct in vitro proteolysis of proposed regulatory substrates (PTEN, IkBa, Parkin) by reconstituted immunoproteasome","Free versus assembled PSMB10 contributions not separated across disease contexts"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[3,11]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[3,12]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,11]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[16]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,3,17]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4,16]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[8,14]}],"complexes":["immunoproteasome","20S proteasome"],"partners":["PSMB9","PSMB8","PTEN","PARKIN","E1A","CSFV NS3"],"other_free_text":[]}},"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 tissue","ntpm":136.3}],"url":"https://www.proteinatlas.org/search/PSMB10"},"hgnc":{"alias_symbol":["LMP10","MGC1665","beta2i"],"prev_symbol":["MECL1"]},"alphafold":{"accession":"P40306","domains":[{"cath_id":"3.60.20.10","chopping":"40-228","consensus_level":"high","plddt":96.5213,"start":40,"end":228}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P40306","model_url":"https://alphafold.ebi.ac.uk/files/AF-P40306-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P40306-F1-predicted_aligned_error_v6.png","plddt_mean":90.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PSMB10","jax_strain_url":"https://www.jax.org/strain/search?query=PSMB10"},"sequence":{"accession":"P40306","fasta_url":"https://rest.uniprot.org/uniprotkb/P40306.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P40306/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P40306"}},"corpus_meta":[{"pmid":"9256419","id":"PMC_9256419","title":"The subunits MECL-1 and LMP2 are mutually required for incorporation into the 20S proteasome.","date":"1997","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/9256419","citation_count":171,"is_preprint":false},{"pmid":"8786291","id":"PMC_8786291","title":"Identification of MECL-1 (LMP-10) as the third IFN-gamma-inducible proteasome subunit.","date":"1996","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/8786291","citation_count":148,"is_preprint":false},{"pmid":"10878350","id":"PMC_10878350","title":"Overexpression of the proteasome subunits LMP2, LMP7, and MECL-1, but not PA28 alpha/beta, enhances the presentation of an immunodominant lymphocytic choriomeningitis virus T cell epitope.","date":"2000","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/10878350","citation_count":96,"is_preprint":false},{"pmid":"29507100","id":"PMC_29507100","title":"Novel Role for the Immunoproteasome Subunit PSMB10 in Angiotensin II-Induced Atrial Fibrillation in Mice.","date":"2018","source":"Hypertension (Dallas, Tex. : 1979)","url":"https://pubmed.ncbi.nlm.nih.gov/29507100","citation_count":90,"is_preprint":false},{"pmid":"16547243","id":"PMC_16547243","title":"T cells lacking immunoproteasome subunits MECL-1 and LMP7 hyperproliferate in response to polyclonal mitogens.","date":"2006","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/16547243","citation_count":66,"is_preprint":false},{"pmid":"9174609","id":"PMC_9174609","title":"Molecular cloning of the mouse proteasome subunits MC14 and MECL-1: reciprocally regulated tissue expression of interferon-gamma-modulated proteasome subunits.","date":"1997","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/9174609","citation_count":49,"is_preprint":false},{"pmid":"28478040","id":"PMC_28478040","title":"Knockout of immunoproteasome subunit β2i ameliorates cardiac fibrosis and inflammation in DOCA/Salt hypertensive mice.","date":"2017","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/28478040","citation_count":34,"is_preprint":false},{"pmid":"29499566","id":"PMC_29499566","title":"The immunoproteasome subunit LMP10 mediates angiotensin II-induced retinopathy in mice.","date":"2018","source":"Redox biology","url":"https://pubmed.ncbi.nlm.nih.gov/29499566","citation_count":33,"is_preprint":false},{"pmid":"15547699","id":"PMC_15547699","title":"Expression of HLA class I antigen and proteasome subunits LMP-2 and LMP-10 in primary vs. metastatic breast carcinoma lesions.","date":"2004","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/15547699","citation_count":32,"is_preprint":false},{"pmid":"30657666","id":"PMC_30657666","title":"Structure-Based Design of Inhibitors Selective for Human Proteasome β2c or β2i Subunits.","date":"2019","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30657666","citation_count":29,"is_preprint":false},{"pmid":"10413086","id":"PMC_10413086","title":"Mutational analysis of subunit i beta2 (MECL-1) demonstrates conservation of cleavage specificity between yeast and mammalian proteasomes.","date":"1999","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/10413086","citation_count":23,"is_preprint":false},{"pmid":"24752327","id":"PMC_24752327","title":"Correlation of LMP10 expression and clinical outcome in Human Papillomavirus (HPV) positive and HPV-Negative tonsillar and base of tongue cancer.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24752327","citation_count":19,"is_preprint":false},{"pmid":"37501008","id":"PMC_37501008","title":"The immunoproteasome subunit β2i ameliorates myocardial ischemia/reperfusion injury by regulating Parkin-Mfn1/2-mediated mitochondrial fusion.","date":"2023","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/37501008","citation_count":16,"is_preprint":false},{"pmid":"9367687","id":"PMC_9367687","title":"DNA sequence, chromosomal localization, and tissue expression of the mouse proteasome subunit lmp10 (Psmb10) gene.","date":"1997","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/9367687","citation_count":16,"is_preprint":false},{"pmid":"33195259","id":"PMC_33195259","title":"Deficiency of LMP10 Attenuates Diet-Induced Atherosclerosis by Inhibiting Macrophage Polarization and Inflammation in Apolipoprotein E Deficient Mice.","date":"2020","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/33195259","citation_count":16,"is_preprint":false},{"pmid":"22018786","id":"PMC_22018786","title":"Adenovirus E1A interacts directly with, and regulates the level of expression of, the immunoproteasome component MECL1.","date":"2011","source":"Virology","url":"https://pubmed.ncbi.nlm.nih.gov/22018786","citation_count":16,"is_preprint":false},{"pmid":"33968021","id":"PMC_33968021","title":"The Immunoproteasome Subunits LMP2, LMP7 and MECL-1 Are Crucial Along the Induction of Cerebral Toxoplasmosis.","date":"2021","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33968021","citation_count":16,"is_preprint":false},{"pmid":"22398747","id":"PMC_22398747","title":"A critical role for the inducible proteasomal subunits LMP7 and MECL1 in cytokine production by activated murine splenocytes.","date":"2012","source":"Pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/22398747","citation_count":14,"is_preprint":false},{"pmid":"32581853","id":"PMC_32581853","title":"Deficiency of the Immunoproteasome LMP10 Subunit Attenuates Angiotensin II-Induced Cardiac Hypertrophic Remodeling via Autophagic Degradation of gp130 and IGF1R.","date":"2020","source":"Frontiers in physiology","url":"https://pubmed.ncbi.nlm.nih.gov/32581853","citation_count":11,"is_preprint":false},{"pmid":"19126869","id":"PMC_19126869","title":"Dichotomous haplotypic lineages of the immunoproteasome subunit genes, PSMB8 and PSMB10, in the MHC class I region of a Teleost Medaka, Oryzias latipes.","date":"2009","source":"Molecular biology and evolution","url":"https://pubmed.ncbi.nlm.nih.gov/19126869","citation_count":11,"is_preprint":false},{"pmid":"12324470","id":"PMC_12324470","title":"Identification of functional segments within the beta2I-domain of integrin alphaMbeta2.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12324470","citation_count":10,"is_preprint":false},{"pmid":"12606494","id":"PMC_12606494","title":"Expression and regulation of interferon gamma-inducible proteasomal subunits LMP7 and LMP10 in the bovine corpus luteum.","date":"2002","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/12606494","citation_count":9,"is_preprint":false},{"pmid":"15615722","id":"PMC_15615722","title":"Dual function for a unique site within the beta2I domain of integrin alphaMbeta2.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15615722","citation_count":9,"is_preprint":false},{"pmid":"29856997","id":"PMC_29856997","title":"Anti-viral immune response in the lung and thymus: Molecular characterization and expression analysis of immunoproteasome subunits LMP2, LMP7 and MECL-1 in pigs.","date":"2018","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/29856997","citation_count":9,"is_preprint":false},{"pmid":"31493657","id":"PMC_31493657","title":"Host cell protein PSMB10 interacts with viral NS3 protein and inhibits the growth of classical swine fever virus.","date":"2019","source":"Virology","url":"https://pubmed.ncbi.nlm.nih.gov/31493657","citation_count":7,"is_preprint":false},{"pmid":"23932981","id":"PMC_23932981","title":"Anti-viral immune responses in a primitive lung: characterization and expression analysis of interferon-inducible immunoproteasome subunits LMP2, LMP7 and MECL-1 in a sarcopterygian fish, the Nigerian spotted lungfish (Protopterus dolloi).","date":"2013","source":"Developmental and comparative immunology","url":"https://pubmed.ncbi.nlm.nih.gov/23932981","citation_count":6,"is_preprint":false},{"pmid":"39734035","id":"PMC_39734035","title":"Thymic and T-cell intrinsic critical roles associated with severe combined immunodeficiency and Omenn syndrome due to a heterozygous variant (G201R) in PSMB10.","date":"2024","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/39734035","citation_count":5,"is_preprint":false},{"pmid":"40462177","id":"PMC_40462177","title":"PSMB10 maintains the stemness of chemotherapeutic drug-resistant leukemia cells by inhibiting senescence and cytotoxic T lymphocyte-mediated killing in a ubiquitinated degradation manner.","date":"2025","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/40462177","citation_count":4,"is_preprint":false},{"pmid":"16965406","id":"PMC_16965406","title":"Genomic organization, localization and polymorphism of porcine PSMB10, a gene encoding the third beta-type proteasome subunit of 26S proteasome complex.","date":"2006","source":"Journal of animal breeding and genetics = Zeitschrift fur Tierzuchtung und Zuchtungsbiologie","url":"https://pubmed.ncbi.nlm.nih.gov/16965406","citation_count":4,"is_preprint":false},{"pmid":"17541830","id":"PMC_17541830","title":"Molecular characterization, expression and mapping of porcine LMP2 and MECL-1 genes.","date":"2007","source":"DNA sequence : the journal of DNA sequencing and mapping","url":"https://pubmed.ncbi.nlm.nih.gov/17541830","citation_count":2,"is_preprint":false},{"pmid":"41971628","id":"PMC_41971628","title":"Dominant-negative PSMB10 disrupts immunoproteasome assembly and leads to transient T lymphopenia.","date":"2026","source":"Journal of human immunity","url":"https://pubmed.ncbi.nlm.nih.gov/41971628","citation_count":0,"is_preprint":false},{"pmid":"42170594","id":"PMC_42170594","title":"Novel de novo dominant PSMB10 variants in three patients with immune deficiency and liver disease.","date":"2025","source":"Journal of human immunity","url":"https://pubmed.ncbi.nlm.nih.gov/42170594","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.06.25.25330124","title":"Complexome profiling showed impaired immunoproteasome assembly in a novel PRAAS subtype caused by monoallelic PSMB8 variants","date":"2025-06-26","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.25.25330124","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":19011,"output_tokens":5180,"usd":0.067366,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13495,"output_tokens":4877,"usd":0.0947,"stage2_stop_reason":"end_turn"},"total_usd":0.162066,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"MECL-1 (PSMB10) incorporation into the 20S proteasome is directly dependent on LMP2 expression, and conversely, LMP2 incorporation is strongly enhanced by MECL-1 expression. MECL-1 replaces the constitutive subunit Z upon incorporation. This obligatory co-incorporation occurs at the level of proteasome precursor formation.\",\n      \"method\": \"Cotransfection experiments, immunoprecipitation of proteasome complexes, analysis of precursor assembly\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal dependency demonstrated by cotransfection and proteasome complex analysis, replicated in same study with multiple conditions and confirmed by precursor formation analysis\",\n      \"pmids\": [\"9256419\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"MECL-1 (LMP10/PSMB10) is the third IFN-gamma-inducible proteasome beta subunit; its transcription is increased by IFN-gamma, and it is incorporated into proteasomes while reducing incorporation of constitutive subunits (LMP-9, LMP-17, LMP-19). Together with LMP2 and LMP7, it constitutes the catalytic sites of the immunoproteasome.\",\n      \"method\": \"2D gel electrophoresis of proteasome-associated proteins, Northern blot analysis of IFN-gamma-treated cells\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — biochemical identification of protein incorporation and transcriptional regulation by IFN-gamma, replicated across multiple studies\",\n      \"pmids\": [\"8786291\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"MECL-1 (PSMB10) mRNA is predominantly expressed in thymus, lymph nodes, and spleen (lymphoid tissues), with reciprocal expression to its constitutive counterpart MC14 — tissues with high MECL-1 have low MC14 and vice versa. This reciprocal pattern was reflected in the subunit protein composition of purified 20S proteasomes from liver, thymus, and lung.\",\n      \"method\": \"Northern blot analysis of mouse tissues, purification and analysis of 20S proteasomes from liver, thymus, and lung\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — tissue expression and proteasome protein composition confirmed by two orthogonal methods (Northern blot + proteasome purification), single lab\",\n      \"pmids\": [\"9174609\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"MECL-1 (PSMB10) is autocatalytically processed: a catalytically inactive mutant MECL-1 was incorporated into proteasomes but showed incomplete prosequence removal. The MC14/MECL-1 active sites are specifically responsible for proteasomal trypsin-like activity, with no effect on other catalytic activities upon their loss.\",\n      \"method\": \"Mutagenesis of the active site, stable cell line expression, functional proteasome activity assays\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — active-site mutagenesis combined with functional activity assays, direct demonstration of autocatalytic processing and trypsin-like activity assignment\",\n      \"pmids\": [\"10413086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Overexpression of all three inducible subunits (LMP2, LMP7, MECL-1) together in triple transfectants markedly enhanced MHC class I 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.\",\n      \"method\": \"Triple transfection to form immunoproteasomes, in vitro proteasome degradation assays, MHC class I antigen presentation assays\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro reconstitution of immunoproteasome activity combined with cell-based antigen presentation assay, two orthogonal methods\",\n      \"pmids\": [\"10878350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"T cells lacking both MECL-1 (PSMB10) and LMP7 (but not cells lacking only one subunit) hyperproliferate in response to polyclonal mitogens, with accelerated cell cycling in both CD4+ and CD8+ T cells. This demonstrates an immunoproteasome-specific role in T cell proliferation independent of MHC class I antigen processing.\",\n      \"method\": \"Double knockout mouse model, in vitro mitogen stimulation, cell proliferation and cell cycle analysis, flow cytometry\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined cellular phenotype, epistasis analysis showing the effect requires loss of both subunits, single lab\",\n      \"pmids\": [\"16547243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Adenovirus E1A directly interacts with the immunoproteasome subunit MECL-1 (PSMB10), but binds poorly to the constitutive beta2 subunit it replaces. Binding sites on E1A for MECL-1 map to the N-terminal region and conserved region 3. E1A causes downregulation of MECL-1 expression (as well as LMP2 and LMP7) induced by IFN-gamma, acting via reduction of IFN-gamma-stimulated STAT1 phosphorylation.\",\n      \"method\": \"Co-immunoprecipitation, binding domain mapping, Western blot analysis of expression levels, STAT1 phosphorylation assays\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding confirmed by Co-IP with domain mapping, mechanism via STAT1 supported by western blot, single lab\",\n      \"pmids\": [\"22018786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"LMP7 and MECL-1 (PSMB10) together regulate cytokine expression including IFN-gamma, IL-4, IL-10, IL-2Rb, GATA3, and t-bet in activated splenocytes, while regulation of IL-2, IL-13, TNF-alpha, and IL-2Ra by the proteasome occurs independently of these subunits.\",\n      \"method\": \"LMP7/MECL1 double-knockout mouse splenocytes, PMA/ionomycin stimulation, quantitative RT-PCR for cytokine mRNA\",\n      \"journal\": \"Pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean KO with specific cytokine phenotype, but single method (mRNA quantification) and single lab\",\n      \"pmids\": [\"22398747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PSMB10 (LMP10/beta2i) promotes Ang II-induced atrial fibrillation by degrading PTEN and activating AKT1, which activates TGF-beta-Smad2/3 (leading to cardiac fibrosis) and IKKbeta-mediated ubiquitin-dependent IkBa degradation (leading to NF-kB activation and upregulation of IL-1b, IL-6, NOX2, NOX4, and CX43). PSMB10 trypsin-like activity was increased in atrial tissue and serum.\",\n      \"method\": \"PSMB10 knockout mice and rAAV9-PSMB10 overexpression mice, Ang II infusion model, IKKb inhibitor treatment, Western blot for pathway components, reactive oxygen species measurement, histological analysis\",\n      \"journal\": \"Hypertension (Dallas, Tex. : 1979)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO and overexpression with defined molecular pathway, multiple pathway components analyzed, single lab\",\n      \"pmids\": [\"29507100\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"LMP10 (PSMB10) upregulation in retina promotes PTEN degradation and activation of AKT/IKK signaling, leading to IkBa phosphorylation and degradation and NF-kB target gene activation in Ang II-induced retinopathy.\",\n      \"method\": \"LMP10 KO mice, rAAV2-LMP10 intravitreal injection, IKKb inhibitor treatment, Western blot for signaling pathway components, pathological staining\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO and overexpression with defined signaling pathway, consistent with parallel AF study from same lab\",\n      \"pmids\": [\"29499566\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Beta2i (PSMB10) knockout ameliorates DOCA/salt-induced cardiac fibrosis and inflammation by inhibiting IkBa/NF-kB and TGF-beta1/Smad2/3 signaling pathways.\",\n      \"method\": \"Beta2i knockout mice, DOCA/salt hypertension model, echocardiography, histological staining, Western blot, qRT-PCR\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean KO with defined pathway, but single lab, primarily KO phenotype without mechanistic dissection of direct vs indirect effects\",\n      \"pmids\": [\"28478040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PSMB10 directly interacts with CSFV NS3 protein and degrades it through the ubiquitin-proteasome system, inhibiting viral replication. PSMB10 also restores MHC class I antigen presentation function suppressed by CSFV.\",\n      \"method\": \"Yeast two-hybrid screening, co-immunoprecipitation, GST pulldown, laser confocal microscopy, overexpression/knockdown experiments, viral replication assays\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — interaction confirmed by three orthogonal methods (Y2H, Co-IP, GST pulldown), functional consequence demonstrated, single lab\",\n      \"pmids\": [\"31493657\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Crystal structures of beta2i (PSMB10/MECL-1)-humanized yeast proteasomes with selective inhibitors revealed significant structural differences in the S1 substrate-binding pocket between beta2c and beta2i subunits, enabling rational design of selective inhibitors (LU-002i with IC50 220 nM for beta2i, 45-fold selectivity over beta2c).\",\n      \"method\": \"X-ray crystallography (co-crystal structures), organic synthesis, activity-based protein profiling, yeast mutagenesis, enzymatic IC50 measurements\",\n      \"journal\": \"Journal of medicinal chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures with functional validation by mutagenesis and activity-based profiling, multiple orthogonal methods\",\n      \"pmids\": [\"30657666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LMP10 (PSMB10) knockout attenuates Ang II-induced cardiac hypertrophic remodeling via autophagy-dependent degradation of IGF1R and gp130, thereby reducing AKT/mTOR/STAT3/ERK1/2 signaling. In vitro, LMP10 knockdown activated autophagy and increased degradation of IGF1R and gp130; inhibiting autophagy with chloroquine reversed the protective effect.\",\n      \"method\": \"LMP10 KO mice, Ang II infusion, in vitro cardiomyocyte LMP10 knockdown, chloroquine autophagy inhibition, LC3II/I ratio measurement, Western blot for pathway components\",\n      \"journal\": \"Frontiers in physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO plus in vitro rescue experiment with autophagy inhibitor, multiple pathway components, single lab\",\n      \"pmids\": [\"32581853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Myeloid-specific LMP10 deficiency (via bone marrow transplantation) attenuated atherosclerosis and reduced macrophage polarization toward M1 phenotype by decreasing IkBa degradation and NF-kB activation, demonstrating a macrophage-intrinsic role for PSMB10 in NF-kB-mediated inflammation.\",\n      \"method\": \"LMP10 KO mice, ApoE KO atherosclerosis model, bone marrow transplantation for myeloid-specific deletion, in vitro macrophage ox-LDL stimulation, Western blot, flow cytometry\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — myeloid-specific KO by bone marrow transplantation with in vitro confirmation, single lab\",\n      \"pmids\": [\"33195259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Beta2i (PSMB10) expression in cardiomyocytes suppresses the E3 ubiquitin ligase Parkin, thereby preventing degradation of mitofusin 1/2 (Mfn1/2) and maintaining mitochondrial fusion. Loss of beta2i increases Parkin expression, promotes Mfn1/2 degradation, and causes excessive mitochondrial fission leading to enhanced I/R injury.\",\n      \"method\": \"Beta2i KO mice, rAAV9-beta2i overexpression, cardiac I/R model, Western blot for Parkin/Mfn1/Mfn2/Drp1, mitochondrial morphology analysis, cardiac function assessment\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO and overexpression with defined molecular mechanism (Parkin-Mfn1/2 pathway), single lab\",\n      \"pmids\": [\"37501008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A heterozygous PSMB10 G201R variant acts in a dominant-negative fashion to markedly reduce immunoproteasome protein expression (PSMB9 and PSMB10) in PBMCs, EBV-transformed B cells, and fibroblasts, leading to impaired positive selection of CD8 T cells, impaired generation of diverse T cell repertoire, and impaired negative selection of autoreactive T cells. PSMB10 is expressed in cortical and medullary thymic epithelial cells (confirmed by single-cell RNA sequencing of human thymus).\",\n      \"method\": \"Patient immunophenotyping, flow cytometry, immunoblotting, T-cell development in artificial thymic organoids, single-cell RNA sequencing of human thymus\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human genetic variant with functional studies in patient-derived cells and ex vivo thymic organoids, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"39734035\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"De novo dominant-negative PSMB10 variants (p.Asp205Ala and p.Ser208Phe) show poor integration into the proteasome complex and exert a dominant-negative effect on the PSMB9 subunit, leading to combined immune deficiency and liver disease.\",\n      \"method\": \"Whole exome sequencing, protein expression analysis of proteasome complex assembly, clinical immunophenotyping\",\n      \"journal\": \"Journal of human immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — proteasome complex assembly analysis in patient cells, single lab, limited mechanistic detail in abstract\",\n      \"pmids\": [\"42170594\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A de novo dominant-negative PSMB10 p.G209R mutation impairs immunoproteasome assembly and function (confirmed by molecular modeling and biochemical studies), leading to defective viral sensing and antigen presentation signatures in IFN-treated fibroblasts.\",\n      \"method\": \"Molecular modeling, proteomics, transcriptomics, biochemical proteasome assembly assays, ex vivo T lymphopoiesis, Western blot\",\n      \"journal\": \"Journal of human immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — molecular modeling plus biochemical confirmation with functional consequences in patient fibroblasts, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"41971628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PSMB10 knockdown in AML cells boosts SLC22A16-mediated drug endocytosis and induces chemotherapy drug-mediated senescence through the RPL6/RPS6-MDM2-P21 pathway, while also preventing MHC-I protein degradation and thereby reducing escape from cytotoxic T lymphocyte killing.\",\n      \"method\": \"siRNA knockdown, lentivirus transduction, co-immunoprecipitation, luciferase reporter assays, polysome profiling, quantitative proteomics, xenograft and syngeneic bone marrow transplantation mouse models, flow cytometry\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (proteomics, Co-IP, in vivo models), mechanistic pathway defined, single lab\",\n      \"pmids\": [\"40462177\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PSMB10 (MECL-1/LMP10/beta2i) is an IFN-gamma-inducible catalytic beta subunit of the immunoproteasome that replaces the constitutive MC14/Z subunit and is obligatorily co-incorporated with LMP2 during proteasome precursor assembly; its autocatalytically processed active site confers the trypsin-like proteolytic activity of the immunoproteasome, enabling enhanced MHC class I antigen presentation. Beyond antigen processing, PSMB10 regulates NF-kB signaling (by controlling IkBa degradation), mitochondrial fusion (by suppressing Parkin-mediated Mfn1/2 degradation), T cell proliferation, and cytokine production, and dominant-negative mutations in PSMB10 disrupt immunoproteasome assembly causing severe combined immunodeficiency through impaired thymic selection.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PSMB10 (MECL-1/LMP10/beta2i) is an IFN-gamma-inducible catalytic beta subunit of the immunoproteasome that substitutes for the constitutive subunit Z/MC14 and confers the trypsin-like proteolytic activity of the assembled complex [#1, #3]. Its incorporation into 20S proteasome precursors is reciprocally coupled to LMP2, such that each subunit's assembly depends on co-expression of the other [#0], and PSMB10 itself is autocatalytically processed during maturation [#3]. Crystallographic analysis localizes its catalytic specificity to a distinct S1 substrate-binding pocket that differs from the constitutive beta2 subunit [#12]. Functionally, the immunoproteasome containing PSMB10 enhances generation of MHC class I antigen precursors and antigen presentation [#4], and PSMB10 is preferentially expressed in lymphoid tissues including thymic epithelium [#2, #16]. Beyond antigen processing, PSMB10 governs T cell proliferation and cytokine production together with LMP7 [#5, #7], and shapes inflammatory and fibrotic signaling by promoting IkBa/NF-kB activation, PTEN-AKT signaling, and TGF-beta-Smad2/3 output in cardiovascular and retinal disease models [#8, #9, #10, #14]. It additionally regulates mitochondrial fusion by suppressing Parkin-mediated degradation of mitofusins [#15] and modulates autophagy-dependent receptor turnover [#13]. Dominant-negative PSMB10 variants that disrupt immunoproteasome assembly and the partner subunit PSMB9 cause combined immunodeficiency through impaired thymic T cell selection [#16, #17, #18].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Establishing that PSMB10 is the third IFN-gamma-inducible catalytic subunit defined the molecular composition of the immunoproteasome and placed PSMB10 at its catalytic core alongside LMP2 and LMP7.\",\n      \"evidence\": \"2D gel electrophoresis of proteasome subunits and Northern blot of IFN-gamma-treated cells\",\n      \"pmids\": [\"8786291\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve assembly order or interdependence with other inducible subunits\", \"Catalytic activity contribution not yet assigned\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Demonstrating reciprocal co-incorporation dependency between MECL-1 and LMP2 at the precursor stage revealed that immunoproteasome assembly is a cooperative, ordered process rather than independent subunit swapping, and that PSMB10 replaces the constitutive Z subunit.\",\n      \"evidence\": \"Cotransfection and immunoprecipitation of proteasome complexes with precursor assembly analysis\",\n      \"pmids\": [\"9256419\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the dependency not defined\", \"Did not address how LMP7 fits into the assembly hierarchy\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Mapping reciprocal expression of MECL-1 versus constitutive MC14 across tissues established that immunoproteasome content is set at the tissue level, concentrating PSMB10 function in lymphoid organs.\",\n      \"evidence\": \"Northern blot of mouse tissues and purification of 20S proteasomes from liver, thymus, and lung\",\n      \"pmids\": [\"9174609\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cell-type-resolved expression within tissues not determined\", \"Functional consequence of tissue-specific composition not tested\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Active-site mutagenesis showing autocatalytic processing and assigning trypsin-like activity to the MC14/MECL-1 site defined the specific proteolytic contribution of PSMB10 to the proteasome.\",\n      \"evidence\": \"Active-site mutagenesis with stable cell lines and proteasome activity assays\",\n      \"pmids\": [\"10413086\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Substrate repertoire of trypsin-like activity not enumerated\", \"Catalytically inactive mutant still incorporated, leaving role of catalysis in assembly unresolved\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Reconstituting full immunoproteasomes and showing enhanced epitope precursor generation connected PSMB10-containing complexes mechanistically to improved MHC class I antigen presentation.\",\n      \"evidence\": \"Triple transfection with in vitro degradation assays and cell-based antigen presentation\",\n      \"pmids\": [\"10878350\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"PSMB10-specific contribution not separable from LMP2/LMP7 in the triple transfectant\", \"Generality across diverse epitopes not established\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Double-knockout T cell hyperproliferation revealed an immunoproteasome function in controlling T cell cycling that is independent of antigen processing, requiring combined loss of MECL-1 and LMP7.\",\n      \"evidence\": \"LMP7/MECL-1 double-knockout mice with mitogen stimulation and cell cycle analysis\",\n      \"pmids\": [\"16547243\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular substrate controlling proliferation not identified\", \"Single-subunit contribution masked by epistasis\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defining a specific subset of cytokines regulated by LMP7/MECL-1 distinguished immunoproteasome-dependent from proteasome-general control of T cell effector programs.\",\n      \"evidence\": \"Double-knockout splenocytes with PMA/ionomycin stimulation and qRT-PCR\",\n      \"pmids\": [\"22398747\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"mRNA-only readout without protein-level or mechanistic dissection\", \"Direct substrates linking PSMB10 to GATA3/t-bet not identified\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identifying direct E1A binding to MECL-1 and IFN-gamma-induced downregulation via STAT1 revealed that viruses target PSMB10 directly to suppress immunoproteasome formation.\",\n      \"evidence\": \"Co-IP with binding domain mapping and STAT1 phosphorylation assays\",\n      \"pmids\": [\"22018786\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of E1A-MECL-1 binding for antigen presentation not quantified\", \"Single lab, single viral protein\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Co-crystal structures of beta2i-humanized proteasomes resolved the S1 pocket differences between beta2i and beta2c, providing the structural basis for the trypsin-like specificity and selective inhibitor design.\",\n      \"evidence\": \"X-ray crystallography with activity-based profiling, yeast mutagenesis, and IC50 measurement of selective inhibitor LU-002i\",\n      \"pmids\": [\"30657666\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Human full-length immunoproteasome structure with native beta2i not solved\", \"In vivo selectivity of inhibitors not addressed here\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrating direct PSMB10 interaction with and degradation of CSFV NS3 extended PSMB10 function to direct antiviral restriction beyond antigen processing.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, GST pulldown, confocal microscopy, and viral replication assays\",\n      \"pmids\": [\"31493657\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether degradation requires immunoproteasome assembly versus free PSMB10 not resolved\", \"Single virus, single lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Loss- and gain-of-function studies in hypertension models defined a PSMB10-driven PTEN degradation/AKT-IKK-NF-kB and TGF-beta-Smad axis driving fibrosis and inflammation in cardiac and retinal tissue.\",\n      \"evidence\": \"PSMB10 KO and rAAV overexpression mice in Ang II and DOCA/salt models with IKKb inhibitor and pathway Western blots\",\n      \"pmids\": [\"29507100\", \"29499566\", \"28478040\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct proteolytic versus indirect regulation of PTEN/IkBa not biochemically separated\", \"All from related model systems and single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Tissue- and cell-specific studies extended PSMB10's NF-kB and degradation roles to autophagy-dependent receptor turnover in hypertrophy and to macrophage-intrinsic M1 polarization in atherosclerosis.\",\n      \"evidence\": \"LMP10 KO mice with in vitro knockdown, chloroquine autophagy inhibition, and myeloid-specific deletion by bone marrow transplantation\",\n      \"pmids\": [\"32581853\", \"33195259\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which PSMB10 represses autophagy not defined\", \"Direct substrates (IGF1R, gp130) versus indirect effects not biochemically established\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Linking beta2i to suppression of Parkin and preservation of mitofusins revealed a role in maintaining mitochondrial fusion and protecting against ischemia-reperfusion injury.\",\n      \"evidence\": \"Beta2i KO and rAAV overexpression mice in cardiac I/R with mitochondrial morphology and Parkin/Mfn1/2/Drp1 Western blots\",\n      \"pmids\": [\"37501008\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether PSMB10 controls Parkin directly through proteolysis not shown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identifying a dominant-negative PSMB10 variant that collapses immunoproteasome expression and disrupts thymic T cell selection established PSMB10 as a cause of human immunodeficiency and confirmed its thymic epithelial expression.\",\n      \"evidence\": \"Patient immunophenotyping, immunoblotting, artificial thymic organoids, and single-cell RNA sequencing of human thymus\",\n      \"pmids\": [\"39734035\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural mechanism of dominant-negative interference not fully resolved\", \"Single patient/variant\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Additional de novo dominant-negative variants showing poor proteasome integration and interference with PSMB9 consolidated PSMB10 deficiency as a combined immune deficiency caused by failed immunoproteasome assembly.\",\n      \"evidence\": \"Whole exome sequencing, proteasome assembly assays, molecular modeling, and patient-cell functional studies\",\n      \"pmids\": [\"42170594\", \"41971628\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Quantitative structural basis of dominant-negative effect on PSMB9 not fully defined\", \"Liver disease mechanism unexplained\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrating that PSMB10 knockdown enhances drug-induced senescence and limits MHC-I degradation in AML positioned PSMB10 as a modulator of chemosensitivity and immune escape in cancer.\",\n      \"evidence\": \"siRNA/lentiviral knockdown, Co-IP, polysome profiling, proteomics, and xenograft/syngeneic mouse models\",\n      \"pmids\": [\"40462177\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct PSMB10 substrates in the RPL6/RPS6-MDM2-P21 axis not mapped\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved which of PSMB10's non-antigen-processing roles (NF-kB, PTEN/AKT, Parkin, autophagy) reflect direct proteolytic substrates of its trypsin-like site versus indirect consequences of altered proteasome composition.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct in vitro proteolysis of proposed regulatory substrates (PTEN, IkBa, Parkin) by reconstituted immunoproteasome\", \"Free versus assembled PSMB10 contributions not separated across disease contexts\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [3, 11]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [3, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 11]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 3, 17]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4, 16]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [8, 14]}\n    ],\n    \"complexes\": [\"immunoproteasome\", \"20S proteasome\"],\n    \"partners\": [\"PSMB9\", \"PSMB8\", \"PTEN\", \"Parkin\", \"E1A\", \"CSFV NS3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":7,"faith_pct":85.71428571428571}}