Affinage

PSMB8

Proteasome subunit beta type-8 · UniProt P28062

Length
276 aa
Mass
30.4 kDa
Annotated
2026-04-28
100 papers in source corpus 37 papers cited in narrative 36 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PSMB8 (LMP7/β5i) encodes the inducible chymotrypsin-like catalytic subunit of the immunoproteasome, replacing the constitutive β5 subunit upon IFN-γ stimulation (transcriptionally driven by IRF-1) to shift proteasomal cleavage specificity toward hydrophobic and basic C-termini, thereby optimizing peptide generation for MHC class I antigen presentation (PMID:7937744, PMID:8066463, PMID:15907481). PSMB8 is synthesized as a proprotein whose N-terminal propeptide is cleaved during assembly within 13–16S precursor complexes, where it functions as a maturation chaperone to accelerate immunoproteasome biogenesis (PMID:8458375, PMID:8120905, PMID:22768135). Beyond antigen processing, PSMB8 promotes IκBα degradation to activate NF-κB signaling, thereby regulating proinflammatory cytokine production, Th1/Th17 differentiation, and macrophage pyroptosis, and targets specific substrates including ATG5, ATRAP, and PTEN for degradation to modulate autophagy, cardiac hypertrophy, and vascular remodeling (PMID:20581238, PMID:22984077, PMID:31086810, PMID:30571551, PMID:31629736). Homozygous loss-of-function mutations in PSMB8 cause proteasome-associated autoinflammatory syndromes including JMP syndrome and Nakajo-Nishimura syndrome, characterized by impaired immunoproteasome assembly, accumulation of ubiquitinated proteins, and systemic inflammation (PMID:21129723, PMID:21852578).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1993 High

    Establishing that PSMB8 ortholog PRE2 is the catalytic subunit responsible for chymotrypsin-like activity of the 20S proteasome resolved the identity of the active site performing this cleavage specificity, and demonstrating propeptide processing of LMP7 revealed a previously unknown maturation step for proteasome subunits.

    Evidence Yeast complementation cloning with enzymatic assays (PRE2); pulse-chase immunoprecipitation in mammalian cell lines (propeptide cleavage)

    PMID:8383129 PMID:8458375

    Open questions at the time
    • Catalytic mechanism of propeptide self-cleavage not resolved
    • Whether propeptide has functions beyond being removed was unknown
  2. 1994 High

    Demonstration that LMP7 knockout mice have reduced MHC class I surface expression (rescuable by exogenous peptides) and that LMP7 incorporation increases Vmax for hydrophobic/basic cleavages established LMP7 as a peptide supply enzyme that shapes the immunopeptidome for class I presentation.

    Evidence LMP7 knockout mouse with peptide rescue experiments; fluorogenic substrate kinetic assays in transfected cells; pulse-chase assembly analysis in 13–16S precursors

    PMID:7937744 PMID:8066463 PMID:8120905

    Open questions at the time
    • Whether LMP7 alone is sufficient or requires LMP2/MECL-1 cooperation for full effect
    • Identity of specific in vivo peptide products shaped by LMP7
  3. 1995 High

    Reconstitution experiments showed that LMP2 and LMP7 together induce positive cooperativity among proteasome subunits and that PA28 acts by a distinct mechanism, resolving the question of how immunoproteasome components and activators independently shape peptide output.

    Evidence In vitro digestion of defined polypeptide substrates with HPLC/mass spectrometry product analysis; Hill coefficient kinetic analysis

    PMID:7559557 PMID:7589133

    Open questions at the time
    • Whether cooperative effects occur in intact cells or are an in vitro property
    • Structural basis for inter-subunit cooperativity unknown
  4. 1996 High

    Showing that constitutive β5 (X subunit) opposes LMP7 effects and competitively excludes LMP2 established that proteasome specificity is governed by reciprocal subunit exchange rather than simple addition of immunosubunits.

    Evidence Transfection of constitutive X subunit into HeLa cells with 2D-PAGE composition analysis and fluorogenic activity assays

    PMID:8663318

    Open questions at the time
    • Mechanism governing competitive incorporation priority unknown
    • Whether intermediate mixed proteasomes with partial subunit exchange are functional
  5. 2000 High

    Discovery that the LMP7 propeptide accelerates proteasome maturation (acting as a chaperone within POMP-containing precursors) and that immunoproteasomes with all three inducible subunits markedly enhance epitope presentation resolved how assembly kinetics and subunit composition together determine antigen processing efficiency.

    Evidence Propeptide deletion mutants in T2 cells with sucrose gradient fractionation; triple-transfectant antigen presentation assays with in vitro digestion

    PMID:10878350 PMID:10926487

    Open questions at the time
    • Structure of the 13–16S precursor complex not determined
    • Precise chaperone mechanism of propeptide unresolved
  6. 2005 High

    Identification of IRF-1 as the pivotal transcription factor for IFN-γ-dependent LMP7 expression resolved the transcriptional control mechanism linking interferon signaling to immunoproteasome induction.

    Evidence Tetracycline-inducible IRF-1, siRNA knockdown, IRF-1 knockout mice, reporter assays

    PMID:15907481

    Open questions at the time
    • Whether additional transcription factors cooperate with IRF-1 at the LMP7 locus
    • Chromatin-level regulation not characterized
  7. 2010 High

    LMP7 knockout mice showed attenuated colitis with reduced NF-κB signaling and Th1/Th17 expansion, establishing that PSMB8 functions as a pro-inflammatory mediator beyond its role in antigen presentation, and identification of the T75M mutation causing JMP syndrome linked PSMB8 loss-of-function to human autoinflammatory disease.

    Evidence DSS colitis in LMP7 KO mice with NF-κB and cytokine readouts; homozygosity mapping and chymotrypsin-like activity assays in patient lymphoblasts

    PMID:20581238 PMID:21129723

    Open questions at the time
    • Molecular substrate(s) of PSMB8 mediating NF-κB activation not identified at this point
    • Whether JMP syndrome involves immunoproteasome-independent mechanisms
  8. 2011 High

    Characterization of additional PSMB8 mutations (G201V, G197V) causing Nakajo-Nishimura syndrome and lipodystrophy revealed that impaired β5i incorporation into immunoproteasomes causes ubiquitinated/oxidized protein accumulation and aberrant cytokine production, and demonstrated an unexpected role for PSMB8 in adipocyte differentiation.

    Evidence Patient cell immunoproteasome assembly analysis, ubiquitinated protein assays, adipocyte differentiation assays in vitro and in vivo siRNA

    PMID:21852578 PMID:21881205

    Open questions at the time
    • Mechanism by which immunoproteasome dysfunction drives lipodystrophy remains unclear
    • Whether proteotoxic stress or signaling defect is the primary driver of disease pathology
  9. 2012 High

    Propeptide swap experiments showed proLMP7 has superior chaperone activity over proβ5 for immunoproteasome maturation, and pharmacological/genetic studies demonstrated PSMB8 controls Th cell polarization via STAT3/STAT1/SMAD phosphorylation, refining the mechanism of immune regulation.

    Evidence Propeptide swap constructs in LMP7-deficient cells and mice; ONX 0914 inhibition and LMP7 KO with phospho-STAT/SMAD immunoblots in polarized T cells

    PMID:22768135 PMID:22984077

    Open questions at the time
    • Whether PSMB8 directly degrades STAT regulators or acts indirectly
    • Structural basis for superior chaperone activity of proLMP7 unknown
  10. 2014 High

    Crystal structures of the immunoproteasome revealed exploitable structural differences between β5i and constitutive β5c active sites, enabling development of β5i-selective inhibitors and providing the first atomic-resolution view of the LMP7 catalytic pocket.

    Evidence X-ray crystallography of murine 20S constitutive and immunoproteasome core particles with bound inhibitors, structure-activity relationship studies

    PMID:25006746

    Open questions at the time
    • Human immunoproteasome crystal structure not yet reported at this point
    • How conformational dynamics affect substrate selection in cells
  11. 2018 High

    Multiple studies converged to show that PSMB8 promotes NF-κB activation via IκBα degradation across diverse cell types, with upstream regulation by miR-451 and apelin, and that co-inhibition of both LMP7 and LMP2 is required for full immunomodulatory effects, refining the therapeutic target landscape.

    Evidence Dual-luciferase miR-451 target validation in diabetic nephropathy model; apelin/β5i epistasis in KO mice; selective LMP7-only vs. dual LMP7+LMP2 inhibitor comparison in colitis and EAE models

    PMID:27264074 PMID:30279279 PMID:30301930

    Open questions at the time
    • Whether IκBα is a direct proteolytic substrate of LMP7 or degraded indirectly via ubiquitin-proteasome pathway changes
    • Full spectrum of miRNAs regulating PSMB8 not mapped
  12. 2019 High

    Identification of ATG5, ATRAP, and PTEN as specific degradation targets of PSMB8 established non-immune substrate-specific functions linking immunoproteasome activity to autophagy inhibition, cardiac hypertrophy, vascular remodeling, and retinopathy.

    Evidence Reciprocal co-IP of β5i–ATG5 with KO/OE epistasis in cardiac hypertrophy models; β5i KO restoring ATRAP levels in atrial fibrillation and retinopathy models; PTEN stabilization in β5i KO with pharmacological PTEN inhibitor rescue in DOCA-salt model

    PMID:30571551 PMID:31086810 PMID:31629736 PMID:31636038

    Open questions at the time
    • Whether ATG5/ATRAP/PTEN degradation requires ubiquitination or is direct
    • Whether these substrates are cleaved by β5i catalytic activity or require assembled immunoproteasome
    • Relative contribution of immune vs. non-immune PSMB8 functions in cardiovascular disease
  13. 2021 High

    Development of M3258 as a potent reversible LMP7-selective inhibitor with crystal structure-defined binding mode and demonstrated anti-myeloma activity validated PSMB8 as a druggable oncology target.

    Evidence X-ray co-crystal structures, biochemical selectivity profiling, multiple myeloma xenograft efficacy studies

    PMID:34045234 PMID:34228444

    Open questions at the time
    • Clinical efficacy and safety in patients not yet established
    • Whether LMP7 inhibition induces compensatory constitutive proteasome upregulation in tumors

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include whether IκBα is a direct catalytic substrate of β5i or is degraded indirectly, the structural basis for the propeptide's superior chaperone activity, the full in vivo immunopeptidome shaped by LMP7, and whether intermediate mixed proteasomes containing partial immunosubunit incorporation are physiologically relevant.
  • Direct substrate vs. indirect mechanism for IκBα degradation unresolved
  • No structure of 13–16S precursor complex with propeptide
  • Complete immunopeptidome comparison between LMP7-sufficient and -deficient cells lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 7 GO:0016787 hydrolase activity 6
Localization
GO:0005634 nucleus 1 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 9 R-HSA-168256 Immune System 8 R-HSA-392499 Metabolism of proteins 7 R-HSA-1643685 Disease 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-9612973 Autophagy 1
Partners
ATG5ATRAPHCV NS3POMPPSMB10PSMB9PTEN
Complex memberships
13-16S proteasome precursor complex20S immunoproteasome26S immunoproteasome

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 LMP7 (PSMB8) knockout mice show reduced MHC class I cell-surface expression and inefficient presentation of the endogenous antigen HY; addition of exogenous peptides to LMP7-deficient splenocytes restores wild-type class I expression, demonstrating LMP7 functions in the peptide supply machinery for MHC class I antigen presentation. Targeted gene deletion (knockout mouse), MHC class I surface expression assay, peptide rescue experiment Science High 8066463
1994 LMP7 incorporation into 20S and 26S proteasomes increases Vmax for cleavage after hydrophobic and basic residues without affecting hydrolysis after acidic residues, shifting peptide product profile toward the types of C-termini found on MHC class I-presented peptides. Gene transfection into lymphoblasts/HeLa cells, fluorogenic peptide substrate assays measuring Vmax of 20S and 26S proteasomes Proceedings of the National Academy of Sciences of the United States of America High 7937744
1993 The yeast PRE2 gene (ortholog of human RING10/PSMB8) encodes the proteasomal subunit responsible for chymotrypsin-like activity of the 20S proteasome; pre2 missense mutants accumulate ubiquitinated proteins and are sensitive to stress, establishing this subunit as central to chymotryptic activity and ubiquitinated protein degradation. Complementation cloning of pre2 mutants, in vivo chymotryptic activity assay, ubiquitin-conjugate accumulation assay, stress sensitivity assay The Journal of biological chemistry High 8383129
1994 LMP7 and LMP2 proproteins are processed within 13–16S precursor complexes and only their processed (mature) forms are incorporated into active 20S proteasomes, demonstrating that proteasome assembly occurs via distinct precursor intermediates. Pulse-chase metabolic labeling, sedimentation analysis (sucrose gradient), protein gel electrophoresis of 13–16S vs 20S fractions from mouse T cells Journal of molecular biology High 8120905
1995 Incorporation of LMP2 and LMP7 into 20S proteasomes alters the cleavage site preference and peptide product profile from a polypeptide substrate (murine CMV IE pp89 25-mer) independently of IFN-γ; having both LMP subunits together induces a marked increase in positive cooperativity (Hill coefficient) among proteasome subunits. IFN-γ-independent LMP transfection, dual cleavage assay on polypeptide substrate, fluorogenic peptide substrate kinetic analysis, Hill coefficient determination European journal of immunology High 7589133
1995 The IFN-γ-inducible 11S regulator (PA28) does not preferentially activate LMP7-containing immunoproteasomes, but binding of PA28 to any proteasome preparation markedly changes both the quality and quantity of peptide products generated from a 25-mer substrate, indicating PA28 and LMP7 act by distinct mechanisms. Overexpression of LMP subunits by transfection, in vitro digestion of 25-mer peptide ± purified PA28, HPLC and electrospray mass spectrometry analysis of cleavage products The Journal of biological chemistry High 7559557
1996 Constitutive subunit X (β5c) opposes LMP7 activity: X transfection reduces hydrolysis after hydrophobic and basic residues (opposite to LMP7 effect), and X transfection also increases Y (δ) subunit content while decreasing LMP2 content, showing competitive subunit exchange governs proteasome specificity. Gene transfection of X and Y subunits into HeLa cells, fluorogenic peptide substrate peptidase assays, 2D-PAGE subunit composition analysis The Journal of biological chemistry High 8663318
1993 LMP7 and LMP2 are synthesized as precursor proteins (~30 kDa and ~24 kDa respectively); only the processed forms (23 kDa and 21 kDa) are incorporated into the 20S proteasome complex, with subcellular localization showing strong nuclear localization in thymus cells and even cytoplasmic/nuclear distribution in liver cells. Pulse-chase analysis, Western blot, immunocytology of mouse tissues European journal of biochemistry Medium 8365398
1993 The LMP7 N-terminal propeptide undergoes post-translational cleavage before formation of the mature 23 kDa proteasome subunit, providing the first biochemical evidence for proprotein processing of proteasome components. Pulse-chase experiment, Western blot, anti-LMP7 immunoprecipitation from multiple cell lines European journal of immunology High 8458375
2000 The human proteasome maturation protein POMP (Ump1 homolog) is present only in 16S precursor complexes and not in mature 20S proteasomes; IFN-γ induces POMP expression. The LMP7 propeptide is not essential for incorporation into the proteasome, but its deletion causes delayed proteasome maturation and accumulation of precursor complexes with increased POMP. 2D-gel proteomics of precursor preparations, Northern blot, propeptide deletion/mutation constructs expressed in T2 cells, sucrose gradient fractionation Journal of molecular biology High 10926487
2000 LMP7 is regulated in human endothelial cells by cytokines of cellular immunity: IFN-γ upregulates LMP7 levels, TNF-α upregulates to a lesser extent, while IL-10 downregulates IFN-γ-induced LMP7, and IL-6/IL-12 alone have little effect. Cytokine treatment of human umbilical vein endothelial cells, Western blot for LMP7 protein levels Cytokine Medium 10975991
2000 Overexpression of all three inducible subunits (LMP2, LMP7, MECL-1) in triple transfectants markedly enhances MHC class I-restricted presentation of the LCMV NP118 epitope; in vitro, immunoproteasomes generate higher amounts of N-terminally extended precursors of NP118 compared to constitutive proteasomes. Triple transfection, MHC class I antigen presentation assay with CTLs, in vitro proteasome digestion of polypeptide substrate Journal of immunology High 10878350
2005 IRF-1 (interferon regulatory factor-1) is the pivotal transcription factor mediating IFN-γ-dependent LMP7 expression; a tetracycline-inducible IRF-1 system and siRNA knockdown of IRF-1 (as well as IRF-1−/− mice) confirmed IRF-1 binding to a genomic region controlling LMP7 transcription. Tetracycline-inducible IRF-1 expression, siRNA knockdown, IRF-1 knockout mice, reporter assay, qPCR FEBS letters High 15907481
2004 HCV NS3 protein directly interacts with the prosequence region (aa 1–40) of LMP7 via its protease domain (identified by yeast two-hybrid, in vitro binding, and co-immunoprecipitation); this interaction reduces immunoproteasome peptidase activities in a stable HCV subgenomic replicon cell line without affecting NS3 protease activity. Yeast two-hybrid screen, in vitro binding assay, co-immunoprecipitation, peptidase activity assay in HCV replicon cells The Biochemical journal High 15303969
2010 A homozygous missense mutation c.224C>T (p.Thr75Met) in PSMB8 causes JMP syndrome (joint contractures, muscle atrophy, microcytic anemia, panniculitis-induced lipodystrophy); patient lymphoblasts show significantly reduced chymotrypsin-like immunoproteasome proteolytic activity, and structural modeling indicates the T75M substitution disrupts PSMB8 tertiary structure. Homozygosity mapping, direct sequencing, chymotrypsin-like proteolytic activity assay in patient vs. normal lymphoblasts, structural modeling American journal of human genetics High 21129723
2011 A G201V mutation in PSMB8 disrupts the β-sheet structure near the catalytic threonine and the interface with the β4 subunit, preventing efficient incorporation of β5i into immunoproteasomes during biogenesis, resulting in reduced proteasome activity, accumulation of ubiquitinated and oxidized proteins, elevated IL-6 and IP-10, and increased p38 phosphorylation in patient cells (Nakajo-Nishimura syndrome). PSMB8 sequencing, proteasome assembly analysis (immunoprecipitation), ubiquitinated protein accumulation assay, cytokine ELISA, p38 phosphorylation assay, in vitro and in vivo patient cell analysis Proceedings of the National Academy of Sciences of the United States of America High 21852578
2011 A G197V mutation in PSMB8 increases assembly intermediates of immunoproteasomes, decreasing proteasome function and causing ubiquitin-coupled protein accumulation in patient tissues; knockdown of PSMB8 inhibits differentiation of murine and human adipocytes in vitro, and siRNA injection of Psmb8 in mouse skin reduces adipocyte tissue volume, identifying PSMB8 as a regulator of adipocyte differentiation. Exome sequencing, immunoproteasome assembly intermediate analysis, ubiquitinated protein accumulation assay, adipocyte differentiation assay in vitro and in vivo siRNA injection The Journal of clinical investigation High 21881205
2010 LMP7 (PSMB8) deficiency attenuates DSS-induced colitis through reduced NF-κB signaling, decreased proinflammatory cytokine/chemokine secretion, diminished neutrophil infiltration, and reduced Th1/Th17 T cell expansion in the colon. LMP7 knockout mice, DSS-induced colitis model, NF-κB signaling assay, cytokine profiling, histological analysis Gut High 20581238
2012 LMP7 deficiency or inhibition with ONX 0914 suppresses Th1 and Th17 differentiation while promoting regulatory T cell (Treg) development; mechanistically, immunoproteasome inhibition blocks STAT3 phosphorylation in Th17 conditions and enhances SMAD phosphorylation in Treg conditions, and reduces STAT1 phosphorylation for Th1. LMP7 knockout mice, ONX 0914 pharmacological inhibition, Th cell polarization assays, phospho-STAT3/SMAD/STAT1 immunoblot, DSS colitis and T cell transfer colitis models Journal of immunology High 22984077
2011 LMP7 (β5i) deficiency in coxsackievirus B3 myocarditis leads to severe myocardial tissue damage due to impaired removal of poly-ubiquitinated protein aggregates (proteotoxic stress), impaired NF-κB activation in cardiomyocytes, and increased apoptosis, demonstrating immunoproteasomes protect the heart from excessive inflammatory damage by clearing oxidant-damaged proteins. LMP7 knockout mice, CVB3 infection model, ubiquitinated protein aggregate assay, NF-κB activation assay, adoptive T cell transfer, histological analysis PLoS pathogens High 21909276
2012 The LMP7 propeptide (proLMP7) acts as a chaperone to promote immunoproteasome maturation with significantly higher activity than the constitutive β5 propeptide (proβ5); under inflammatory conditions, proβ5 promotes integration into LMP2/MECL-1-containing precursors (not β1/β2 precursors as previously proposed); LMP7 induction by infection also increases total proteasome abundance in infected tissue. Propeptide swap constructs in LMP7-deficient cells and infected LMP7-deficient mice, proteasome maturation assay, MHC class I surface expression, Western blot of proteasome composition PloS one High 22768135
2019 The immunoproteasome β5i subunit (PSMB8) interacts with and promotes degradation of ATG5 (an autophagy protein), thereby inhibiting autophagy and promoting cardiac hypertrophy; β5i knockout attenuates hypertrophy, while overexpression aggravates it, and ATG5 knockdown or autophagy inhibition reverses the protective effect of β5i knockout. Co-immunoprecipitation (β5i–ATG5 interaction), β5i knockout/transgenic mice, angiotensin II treatment, autophagy assay, ATG5 knockdown, cardiomyocyte hypertrophy readouts Science advances High 31086810
2019 β5i (PSMB8) promotes ATRAP (AT1R-associated protein) degradation, resulting in activation of AT1R-mediated NF-κB signaling, increased NADPH oxidase activity, increased TGF-β1/Smad signaling, and altered expression of Kir2.1 and CX43 in the atria, thereby promoting Ang II-induced atrial remodeling and atrial fibrillation. β5i knockout mice, recombinant AAV9-β5i injection, ATRAP overexpression, co-immunoprecipitation, NF-κB assay, atrial fibrillation recording Hypertension High 30571551
2019 β5i (PSMB8) promotes Ang II-induced retinopathy by promoting ATRAP degradation and activation of AT1R-mediated downstream signals; β5i KO restores Ang II-induced downregulation of ATRAP, and ATRAP overexpression abrogates Ang II-induced retinopathy in Ad-β5i-injected mice. β5i knockout mice, adenovirus-β5i injection, Ad-ATRAP overexpression, Ang II infusion model, retinal histology, Western blot Molecular therapy High 31636038
2019 β5i (PSMB8) deficiency attenuates DOCA-salt-induced cardiac remodeling by preventing PTEN degradation, thereby inhibiting AKT/mTOR, ERK1/2, TGF-β1/Smad2/3, NOX, and NF-κB signaling; PTEN blockade with VO-OHpic reverses the protective effect of β5i knockout, placing β5i upstream of PTEN in cardiac remodeling. β5i knockout mice, DOCA-salt hypertension model, PTEN protein stability assay, pharmacological PTEN inhibitor rescue experiment (VO-OHpic), cardiac echocardiography and histology, signaling pathway Western blots Journal of molecular and cellular cardiology High 31629736
2020 β5i (PSMB8) deletion reduces IκBα degradation and inhibits NF-κB activation, which promotes MERTK (Mer receptor tyrosine kinase) transcription and macrophage efferocytosis of apoptotic cells, thereby attenuating atherosclerosis; pharmacological inhibition with PR-957 or bone marrow transplantation from dKO mice recapitulates these effects. β5i/ApoE double KO mice, bone marrow transplant, PR-957 pharmacological inhibition, IκBα/NF-κB/MERTK pathway assays, efferocytosis assay, atherosclerotic lesion analysis The Journal of pathology High 31758542
2006 Heat shock transcriptionally upregulates lmp2 and lmp7 in mouse and human cells, and heat-shocked cells show enhanced presentation of immunoproteasome-dependent MHC class I epitopes (LCMV NP118-126 and adenovirus E1B192-200) but not immunoproteasome-independent epitopes, linking heat shock response to altered immunoproteasome-dependent antigen processing. Heat shock treatment, RT-PCR for lmp2/lmp7 mRNA, CTL presentation assay with immunoproteasome-dependent vs. independent epitopes Journal of immunology Medium 17142736
2018 miR-451 directly targets LMP7 (PSMB8) mRNA (validated by dual-luciferase reporter assay) to inhibit NF-κB activity and downregulate proinflammatory molecule transcription in mesangial cells under diabetic conditions; increasing miR-451 in db/db mice inhibits the LMP7/NF-κB pathway and attenuates renal injury. Deep sequencing, dual-luciferase reporter assay, Western blot, chromatin immunoprecipitation, in vivo miR-451 delivery in db/db mice Molecular and cellular endocrinology High 27264074
2018 Apelin inhibits β5i (PSMB8) expression in podocytes, which decreases IκB degradation, promotes IκB nuclear translocation, inhibits NF-κB-driven TGF-β expression, and reduces Smad pathway activation and epithelial-mesenchymal transition; β5i knockout mice confirm these effects are β5i-dependent. β5i knockout mice, diabetic mouse model, apelin treatment, IκB/NF-κB assay, TGF-β/Smad pathway, EMT marker analysis Cell death & disease High 30301930
2014 Structure-based design using X-ray crystal structures of murine constitutive and immunoproteasome 20S core particles revealed structural differences between β5c and β5i active sites exploitable for selective inhibitor development; β5i-selective inhibitors were developed that outperform existing leads in potency and selectivity. X-ray crystallography of proteasome–inhibitor complexes, structure-based drug design, biochemical IC50 assays, cell-permeability experiments Journal of medicinal chemistry High 25006746
2021 M3258, a potent reversible LMP7 (β5i/PSMB8)-selective inhibitor, was discovered through structure-based optimization; crystal structures defined non-primed and primed pocket interactions; M3258 causes prolonged suppression of LMP7 activity, inhibits ubiquitinated protein turnover, and induces apoptosis in multiple myeloma cells in vitro and in vivo xenograft models. X-ray crystallography of inhibitor-bound immunoproteasome, biochemical selectivity profiling across all proteasome subunits, multiple myeloma xenograft models, ubiquitinated protein assay Journal of medicinal chemistry / Molecular cancer therapeutics High 34045234 34228444
2018 Co-inhibition of both LMP7 and LMP2 (but not LMP7 alone) is required to impair MHC class I surface expression, inhibit IL-6 secretion, block Th17 differentiation, and strongly ameliorate experimental colitis and EAE; prolonged exposure to ONX 0914 inhibits both LMP7 and LMP2. Selective LMP7-only inhibitor (PRN1126) vs. combined LMP7+LMP2 inhibition, MHC class I surface expression assay, IL-6 secretion assay, Th17 differentiation assay, DSS colitis and EAE mouse models EMBO reports High 30279279
2017 LMP7 (PSMB8) is required in radioresistant thymic cells (most likely medullary thymic epithelial cells) to prevent excessive negative selection of LCMV GP118-125-specific T cell precursors, thereby filling a hole in the CD8+ T cell repertoire; bone marrow chimeras and adoptive transfer of LMP7-deficient CD8+ T cells into RAG1-deficient mice demonstrated the radioresistant cell requirement. LMP7 knockout mice, LCMV infection, bone marrow chimeras, adoptive transfer into RAG1-deficient mice, T cell repertoire analysis European journal of immunology High 29067678
2018 Increased Lmp7 protein levels and activity are found in a mouse model of α-synuclein aggregation and in postmortem human PD/DLB brains; the immunoproteasome degrades α-synuclein aggregates and generates potentially antigenic peptides, linking proteostasis to immune responses in synucleinopathies. Quantitative proteomics of mouse brain with α-synuclein aggregation model, immunoproteasome activity assay in human postmortem brain tissue, α-synuclein degradation assay EBioMedicine Medium 29759483
2020 β5i (PSMB8) promotes macrophage pyroptosis in abdominal aortic aneurysm by activating NF-κB (via IκB degradation), augmenting NLRP3 expression; β5i deficiency or inhibition (PR-957) decreases macrophage pyroptosis in vitro and AAA formation in vivo. β5i knockout mice, β5i-specific inhibitor PR-957, bone marrow-derived macrophage OXLDL model, NLRP3/NF-κB pathway assays, aortic aneurysm histology Biochemical and biophysical research communications Medium 33019975
2022 PSMB8 expression is upregulated in microglia upon manganese exposure; selective PSMB8 inhibition reduces microglial activation, TNF-α, iNOS, and CCL12 production; PERK signaling drives Mn-induced PSMB8 elevation; and PSMB8 inhibition reduces NF-κB p65 phosphorylation, placing PSMB8 downstream of PERK and upstream of NF-κB in Mn-induced neuroinflammation. In vivo Mn exposure mouse model, BV2 microglia in vitro model, selective PSMB8 inhibitor, PERK inhibitor, NF-κB p65 phosphorylation assay, behavioral tests Food and chemical toxicology Medium 35378207

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1994 MHC class I expression in mice lacking the proteasome subunit LMP-7. Science (New York, N.Y.) 465 8066463
1994 Peptidase activities of proteasomes are differentially regulated by the major histocompatibility complex-encoded genes for LMP2 and LMP7. Proceedings of the National Academy of Sciences of the United States of America 277 7937744
2010 PSMB8 encoding the β5i proteasome subunit is mutated in joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy syndrome. American journal of human genetics 254 21129723
2011 Proteasome assembly defect due to a proteasome subunit beta type 8 (PSMB8) mutation causes the autoinflammatory disorder, Nakajo-Nishimura syndrome. Proceedings of the National Academy of Sciences of the United States of America 241 21852578
1993 PRE2, highly homologous to the human major histocompatibility complex-linked RING10 gene, codes for a yeast proteasome subunit necessary for chrymotryptic activity and degradation of ubiquitinated proteins. The Journal of biological chemistry 235 8383129
2011 A mutation in the immunoproteasome subunit PSMB8 causes autoinflammation and lipodystrophy in humans. The Journal of clinical investigation 234 21881205
1995 The interferon-gamma-inducible 11 S regulator (PA28) and the LMP2/LMP7 subunits govern the peptide production by the 20 S proteasome in vitro. The Journal of biological chemistry 202 7559557
2010 Targeting the proteasome: partial inhibition of the proteasome by bortezomib or deletion of the immunosubunit LMP7 attenuates experimental colitis. Gut 149 20581238
1995 Incorporation of major histocompatibility complex--encoded subunits LMP2 and LMP7 changes the quality of the 20S proteasome polypeptide processing products independent of interferon-gamma. European journal of immunology 141 7589133
2020 LncRNA PSMB8-AS1 contributes to pancreatic cancer progression via modulating miR-382-3p/STAT1/PD-L1 axis. Journal of experimental & clinical cancer research : CR 137 32891166
2012 Immunoproteasome subunit LMP7 deficiency and inhibition suppresses Th1 and Th17 but enhances regulatory T cell differentiation. Journal of immunology (Baltimore, Md. : 1950) 132 22984077
1994 20 S proteasomes are assembled via distinct precursor complexes. Processing of LMP2 and LMP7 proproteins takes place in 13-16 S preproteasome complexes. Journal of molecular biology 129 8120905
2003 Total loss of MHC class I in colorectal tumors can be explained by two molecular pathways: beta2-microglobulin inactivation in MSI-positive tumors and LMP7/TAP2 downregulation in MSI-negative tumors. Tissue antigens 127 12694570
1996 Proteasome subunits X and Y alter peptidase activities in opposite ways to the interferon-gamma-induced subunits LMP2 and LMP7. The Journal of biological chemistry 126 8663318
2016 miR-451 suppresses the NF-kappaB-mediated proinflammatory molecules expression through inhibiting LMP7 in diabetic nephropathy. Molecular and cellular endocrinology 103 27264074
2000 Characterisation of the newly identified human Ump1 homologue POMP and analysis of LMP7(beta 5i) incorporation into 20 S proteasomes. Journal of molecular biology 103 10926487
2010 PR-924, a selective inhibitor of the immunoproteasome subunit LMP-7, blocks multiple myeloma cell growth both in vitro and in vivo. British journal of haematology 98 21114484
2000 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. Journal of immunology (Baltimore, Md. : 1950) 96 10878350
1995 Association of LMP2 and LMP7 genes within the major histocompatibility complex with insulin-dependent diabetes mellitus: population and family studies. American journal of human genetics 91 7847389
2014 Structure-based design of β1i or β5i specific inhibitors of human immunoproteasomes. Journal of medicinal chemistry 83 25006746
2019 The immunoproteasome catalytic β5i subunit regulates cardiac hypertrophy by targeting the autophagy protein ATG5 for degradation. Science advances 82 31086810
2011 Impairment of immunoproteasome function by β5i/LMP7 subunit deficiency results in severe enterovirus myocarditis. PLoS pathogens 81 21909276
1994 MHC-encoded proteasome subunits LMP2 and LMP7 are not required for efficient antigen presentation. Journal of immunology (Baltimore, Md. : 1950) 80 8301122
2005 LMP7/TAP2 gene polymorphisms and HPV infection in esophageal carcinoma patients from a high incidence area in China. Carcinogenesis 72 15774487
2018 Co-inhibition of immunoproteasome subunits LMP2 and LMP7 is required to block autoimmunity. EMBO reports 66 30279279
2006 T cells lacking immunoproteasome subunits MECL-1 and LMP7 hyperproliferate in response to polyclonal mitogens. Journal of immunology (Baltimore, Md. : 1950) 65 16547243
2015 Local synthesis of interferon-alpha in lupus nephritis is associated with type I interferons signature and LMP7 induction in renal tubular epithelial cells. Arthritis research & therapy 64 25889472
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2019 Genetic ablation and pharmacological inhibition of immunosubunit β5i attenuates cardiac remodeling in deoxycorticosterone-acetate (DOCA)-salt hypertensive mice. Journal of molecular and cellular cardiology 25 31629736
2018 Apelin inhibited epithelial-mesenchymal transition of podocytes in diabetic mice through downregulating immunoproteasome subunits β5i. Cell death & disease 25 30301930
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2023 Increased expression of the immunoproteasome subunits PSMB8 and PSMB9 by cancer cells correlate with better outcomes for triple-negative breast cancers. Scientific reports 22 36746983
2022 Immunoproteasome subunit PSMB8 regulates microglia-mediated neuroinflammation upon manganese exposure by PERK signaling. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 22 35378207
2020 Immunoproteasome subunit β5i regulates diet-induced atherosclerosis through altering MERTK-mediated efferocytosis in Apoe knockout mice. The Journal of pathology 22 31758542
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2013 A new infant case of Nakajo-Nishimura syndrome with a genetic mutation in the immunoproteasome subunit: an overlapping entity with JMP and CANDLE syndrome related to PSMB8 mutations. Dermatology (Basel, Switzerland) 18 23942189
2021 Emodin alleviates high glucose-induced oxidative stress, inflammation and extracellular matrix accumulation of mesangial cells by the circ_0000064/miR-30c-5p/Lmp7 axis. Journal of receptor and signal transduction research 17 34151713
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2023 HOXD9/miR-451a/PSMB8 axis is implicated in the regulation of cell proliferation and metastasis via PI3K/AKT signaling pathway in human anaplastic thyroid carcinoma. Journal of translational medicine 16 37974228
2021 The Immunoproteasome Subunits LMP2, LMP7 and MECL-1 Are Crucial Along the Induction of Cerebral Toxoplasmosis. Frontiers in immunology 16 33968021
2020 Macrophage pyroptosis is mediated by immunoproteasome subunit β5i (LMP7) in abdominal aortic aneurysm. Biochemical and biophysical research communications 16 33019975
2020 Comparative Assessment of the WNT/β-Catenin Pathway, CacyBP/SIP, and the Immunoproteasome Subunit LMP7 in Various Histological Types of Renal Cell Carcinoma. Frontiers in oncology 16 33330038
2015 Inhibition of the Immunoproteasome Subunit LMP7 with ONX 0914 Ameliorates Graft-versus-Host Disease in an MHC-Matched Minor Histocompatibility Antigen-Disparate Murine Model. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 16 26093043
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2020 Selective Inhibition of the Immunoproteasome β5i Prevents PTEN Degradation and Attenuates Cardiac Hypertrophy. Frontiers in pharmacology 15 32595507
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2020 Structure-Activity Relationships of Noncovalent Immunoproteasome β5i-Selective Dipeptides. Journal of medicinal chemistry 12 33095579
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