Affinage

PSME2

Proteasome activator complex subunit 2 · UniProt Q9UL46

Round 2 corrected
Length
239 aa
Mass
27.4 kDa
Annotated
2026-04-28
49 papers in source corpus 10 papers cited in narrative 10 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PSME2 (PA28β) is an obligate subunit of the PA28αβ heteroheptameric proteasome activator that caps the 20S proteasome and stimulates peptidase activity in an ATP-independent manner, thereby shaping MHC class I antigen processing. PA28β stabilizes the PA28αβ complex and is required for generation of select immunodominant epitopes but is dispensable for general antigen presentation, as demonstrated by double-knockout mice lacking both PA28α and PA28β (PMID:11689430, PMID:10781831). The PA28-activating function is negatively regulated by Naa10p through direct physical interaction with PA28β, independent of Naa10p acetyltransferase activity (PMID:23624078). Beyond canonical proteasome activation, PSME2 suppresses autophagy through BNIP3- and IL-6/STAT3-dependent pathways and modulates cell invasion and inflammatory barrier function in diverse epithelial contexts (PMID:34779489, PMID:40404117, PMID:41211066).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 1996 High

    Establishing the molecular identity of PA28β as a subunit of an ATP-independent 20S proteasome activator resolved how cells enhance proteasomal peptide cleavage without 19S-dependent energy expenditure.

    Evidence Biochemical reconstitution and review of in vitro proteasome activity assays

    PMID:8811196

    Open questions at the time
    • In vivo requirement for antigen processing not yet tested
    • Relative contribution of PA28β versus PA28α to complex formation unknown
    • No structural model of PA28αβ–20S interaction at this point
  2. 2000 Medium

    Demonstrating that overexpressed PA28β alone enhances MHC class I antigen presentation by stabilizing PA28αβ heterocomplexes, rather than forming functional homomers, established PA28β as a limiting factor for immunoproteasome assembly.

    Evidence Stable transfection, immunoprecipitation, and T-cell cytotoxicity assays for antigen presentation

    PMID:10781831

    Open questions at the time
    • Whether PA28β homomers have any residual activity remained unresolved
    • Single-lab finding not independently replicated at the time
  3. 2001 High

    Genetic ablation of both PA28α and PA28β in mice revealed that the PA28αβ complex is required for processing select antigens (e.g., TRP2) but dispensable for general antigen presentation, and implicated hybrid 19S–20S–PA28 proteasomes in protein degradation.

    Evidence PA28α/β double-knockout mice with proteasome activity assays, T-cell responses, and influenza infection challenge

    PMID:11689430

    Open questions at the time
    • Specific epitope-processing rules dictating PA28 dependence were not defined
    • Hybrid proteasome stoichiometry and substrate specificity not structurally resolved
  4. 2012 Medium

    Discovery that PA28β suppresses gastric cancer cell invasion via downregulation of CLIC1 extended PSME2 function beyond proteasome-mediated antigen processing to a tumor-suppressive role in epithelial cell migration.

    Evidence siRNA knockdown and overexpression with Transwell invasion assays, 2D-DIGE proteomics, CLIC1 epistasis rescue

    PMID:22173998

    Open questions at the time
    • Whether CLIC1 downregulation proceeds via proteasomal degradation or transcriptional regulation was not determined
    • Single-lab observation in gastric cancer cells
  5. 2013 High

    Identification of Naa10p as a direct PA28β-binding negative regulator of PA28-dependent proteasome activity, acting independently of its acetyltransferase function, established the first non-proteasomal protein modulator of PA28 function.

    Evidence Co-immunoprecipitation, cell-free reconstitution with purified proteins, acetyltransferase-dead mutant analysis

    PMID:23624078

    Open questions at the time
    • Binding site on PA28β and structural basis of inhibition not mapped
    • Physiological context (which tissues or conditions engage Naa10p–PA28β regulation) undefined
  6. 2016 Medium

    Genetic deletion of PA28αβ protected diabetic mice from renal and retinal microvascular injury by suppressing high-glucose-induced osteopontin and MCP-1, linking PA28-dependent proteasome activity to metabolic disease pathogenesis in perivascular cells.

    Evidence PA28αβ double-knockout mice with STZ-induced diabetes, mesangial cell and pericyte cultures, peptide inhibitor of PA28–20S interaction

    PMID:27830089

    Open questions at the time
    • Specific PA28-dependent proteasomal substrates driving OPN/MCP-1 induction not identified
    • Whether PA28α or PA28β individually contributes was not dissected
  7. 2021 Medium

    Showing that PSME2 inhibits BNIP3-mediated autophagy in renal carcinoma cells linked its proteasome-activator function to autophagic flux regulation and broadened its role to autophagy suppression in cancer biology.

    Evidence siRNA knockdown with Transwell invasion, TEM of autophagosomes, western blot for autophagy markers

    PMID:34779489

    Open questions at the time
    • Whether PSME2 promotes BNIP3 proteasomal degradation or acts indirectly was not resolved
    • Single-cell-line study without in vivo validation
  8. 2025 Medium

    Convergent studies in esophageal cancer and colonic inflammation established that PSME2 suppresses autophagy through IL-6/STAT3 signaling and promotes inflammatory barrier disruption, consolidating a proteasome-activator-independent role for PSME2 in autophagy regulation across tissues.

    Evidence siRNA knockdown combined with STAT3 inhibitor and chloroquine rescue, in vivo nude mouse and DSS-colitis models

    PMID:40404117 PMID:41211066

    Open questions at the time
    • Whether autophagy suppression requires PA28αβ proteasome-activating function or is mediated by a distinct PSME2 mechanism is unknown
    • Direct proteasomal substrates linking PSME2 to IL-6/STAT3 pathway activation not identified
    • Findings from single laboratories, not yet independently replicated

Open questions

Synthesis pass · forward-looking unresolved questions
  • The relationship between PSME2's canonical proteasome-activation function and its emerging autophagy-suppressive and anti-invasive roles remains mechanistically unresolved — whether these non-canonical functions require PA28αβ complex formation and proteasomal substrate turnover, or represent proteasome-independent activities of PSME2, is the central open question.
  • No separation-of-function mutant distinguishing proteasome-activator from autophagy-regulatory roles
  • No structural basis for Naa10p–PA28β or BNIP3–PSME2 interactions
  • Tissue-specific versus universal nature of PSME2 autophagy regulation untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3
Localization
GO:0005829 cytosol 2
Pathway
R-HSA-392499 Metabolism of proteins 3 R-HSA-9612973 Autophagy 3 R-HSA-168256 Immune System 2
Partners
BNIP3CLIC1NAA10PSME1
Complex memberships
Hybrid 19S-20S-PA28 proteasomePA28αβ (11S regulator)

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 PA28 (the heteropolymer of PA28α/PSME1 and PA28β/PSME2) was identified as a regulator of 20S proteasome activity, with the PA28 complex binding to both ends of the 20S proteasome and stimulating its multiple peptidase activities in an ATP-independent manner, distinct from the 19S regulatory complex. Biochemical reconstitution and review of in vitro proteasome activity assays Annual review of biochemistry High 8811196
1999 The mouse genome contains two chromosomal loci encoding PA28β (PSME2): one is the canonical IFNγ-inducible PMSE2 gene with an intron-exon structure, and the second (PMSE2b) is an expressed retrotransposon inserted into a LINE1 element and driven by a LINE1 F-type monomer promoter, yet encodes a protein indistinguishable from the canonical PSME2. Genomic Southern blot, cloning, sequencing, luciferase reporter assays for promoter activity Journal of molecular biology High 10222192
2000 Overexpression of PA28β alone (without PA28α) improved MHC class I antigen presentation of the MCMV pp89 epitope, and this effect was attributed to increased levels of PA28α/β heterocomplexes rather than PA28β homomers acting independently; immunoprecipitation confirmed that PA28β stabilizes PA28αβ complex formation. Stable transfection of PA28β alone or PA28αβ, northern blot, immunoprecipitation, T-cell cytotoxicity assay for antigen presentation Molecular immunology Medium 10781831
2001 In vivo genetic deletion of both PA28α and PA28β revealed that the PA28αβ heteropolymer is required for processing of specific antigens (e.g., melanoma antigen TRP2-derived peptide) but is dispensable for general antigen presentation; additionally, loss of both subunits reduced ATP-dependent proteolytic activity, implicating 'hybrid proteasomes' (20S capped by PA28 on one end and 19S on the other) in protein degradation. Double-knockout mouse generation (PA28α−/−/β−/−), proteasome activity assays, T-cell cytotoxicity assays, influenza infection model The EMBO journal High 11689430
2013 N-α-acetyltransferase 10 protein (Naa10p) physically associates with PA28β (PSME2) and, in a PA28β-dependent manner, also interacts with PA28α; Naa10p negatively regulates PA28-dependent chymotrypsin-like 28S proteasome activity both in cancer cells and in a cell-free reconstituted system with purified proteins, independently of its acetyltransferase activity. Co-immunoprecipitation, cell-free reconstitution with purified proteins, chymotrypsin-like proteasome activity assay, acetyltransferase-dead mutant analysis FEBS letters High 23624078
2012 Knockdown of PA28β (PSME2) enhanced invasion of gastric cancer cells, while overexpression inhibited it; proteomics revealed that PA28β suppresses invasion at least in part by downregulating chloride intracellular channel 1 (CLIC1), as siRNA-mediated knockdown of CLIC1 rescued the increased invasiveness caused by PA28β knockdown. siRNA knockdown, overexpression, Transwell invasion assay, 2D-DIGE proteomics, RNA interference of CLIC1, immunohistochemistry of patient tissue Journal of cellular biochemistry Medium 22173998
2016 Genetic deletion of PA28α and PA28β protected diabetic mice from renal and retinal microvascular injury; in mesangial cells and retinal pericytes from PA28αβ double-knockout mice, high-glucose-induced expression of osteopontin (OPN) and MCP-1 was suppressed; peptides blocking PA28 binding to the 20S proteasome also suppressed OPN induction, indicating that PA28-mediated modulation of proteasome activity in perivascular cells drives diabetic microvascular injury. Double-knockout mouse model, STZ-induced diabetes, renal histology, cultured mesangial cells and retinal pericytes under high glucose, peptide inhibition of PA28–20S interaction, gene expression analysis International journal of nephrology Medium 27830089
2021 Knockdown of PSME2 in clear cell renal cell carcinoma cells reduced their invasive capacity and simultaneously enhanced autophagy; mechanistically, PSME2 was shown to inhibit BNIP3-mediated autophagy, such that loss of PSME2 de-repressed BNIP3-dependent autophagic flux. siRNA knockdown, Transwell invasion assay, western blot, immunofluorescence, transmission electron microscopy of autophagosomes, CCK-8 assay International journal of oncology Medium 34779489
2025 Knockdown of PSME2 in esophageal squamous cell carcinoma (ESCC) cells reduced proliferation, migration, and invasion, and induced autophagy-mediated cell death; mechanistically, PSME2 knockdown suppressed the IL-6/STAT3 signaling pathway, and combined inhibition of PSME2 with the STAT3 inhibitor WP1066 or the autophagy inhibitor chloroquine suppressed tumor growth in vivo, placing PSME2 upstream of IL-6/STAT3-dependent autophagy suppression. siRNA knockdown, STAT3 inhibitor (WP1066), autophagy inhibitor (chloroquine), in vitro proliferation/migration/invasion assays, in vivo subcutaneous nude mouse tumor model Life sciences Medium 40404117
2025 In colonic cells, PSME2 knockdown restored claudin-1 expression suppressed by LPS, reduced pro-inflammatory cytokines (IL-6, TNF-α), and enhanced autophagy flux (increased LC3-II/LC3-I ratio, reduced p62, elevated LC3B puncta); chloroquine treatment reversed the barrier-protective effects of PSME2 silencing, demonstrating that PSME2 promotes intestinal inflammation and barrier disruption through autophagy dysregulation. siRNA knockdown in colonic cell lines, LPS treatment, western blot for tight junction proteins and autophagy markers, immunofluorescence, cytokine measurement, chloroquine rescue experiment; DSS-induced colitis mouse model Open life sciences Medium 41211066

Source papers

Stage 0 corpus · 49 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1996 Structure and functions of the 20S and 26S proteasomes. Annual review of biochemistry 2108 8811196
2005 Towards a proteome-scale map of the human protein-protein interaction network. Nature 2090 16189514
2002 Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein. Nature 1924 12167863
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2003 Broad antiretroviral defence by human APOBEC3G through lethal editing of nascent reverse transcripts. Nature 1236 12808466
2008 Identification of host proteins required for HIV infection through a functional genomic screen. Science (New York, N.Y.) 1165 18187620
2003 DNA deamination mediates innate immunity to retroviral infection. Cell 1150 12809610
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2003 Induction of APOBEC3G ubiquitination and degradation by an HIV-1 Vif-Cul5-SCF complex. Science (New York, N.Y.) 1006 14564014
2003 The cytidine deaminase CEM15 induces hypermutation in newly synthesized HIV-1 DNA. Nature 912 12808465
2013 Landscape of the PARKIN-dependent ubiquitylome in response to mitochondrial depolarization. Nature 870 23503661
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2003 The antiretroviral enzyme APOBEC3G is degraded by the proteasome in response to HIV-1 Vif. Nature medicine 798 14528300
2003 Species-specific exclusion of APOBEC3G from HIV-1 virions by Vif. Cell 763 12859895
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2003 HIV-1 Vif protein binds the editing enzyme APOBEC3G and induces its degradation. Nature medicine 679 14528301
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2008 Large-scale proteomics and phosphoproteomics of urinary exosomes. Journal of the American Society of Nephrology : JASN 607 19056867
2003 HIV-1 Vif blocks the antiviral activity of APOBEC3G by impairing both its translation and intracellular stability. Molecular cell 607 14527406
2003 Hypermutation of HIV-1 DNA in the absence of the Vif protein. Science (New York, N.Y.) 570 12750511
2006 Hsp90 cochaperone Aha1 downregulation rescues misfolding of CFTR in cystic fibrosis. Cell 517 17110338
1994 Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides. Gene 492 8125298
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2003 The Vif protein of HIV triggers degradation of the human antiretroviral DNA deaminase APOBEC3G. Current biology : CB 405 14614829
2001 Anaphase-promoting complex/cyclosome-dependent proteolysis of human cyclin A starts at the beginning of mitosis and is not subject to the spindle assembly checkpoint. The Journal of cell biology 372 11285280
2001 Immunoproteasome assembly and antigen presentation in mice lacking both PA28alpha and PA28beta. The EMBO journal 132 11689430
2012 PA28β regulates cell invasion of gastric cancer via modulating the expression of chloride intracellular channel 1. Journal of cellular biochemistry 34 22173998
2024 PSME2 offers value as a biomarker of M1 macrophage infiltration in pan-cancer and inhibits osteosarcoma malignant phenotypes. International journal of biological sciences 21 38385075
2021 Increased expression of PSME2 is associated with clear cell renal cell carcinoma invasion by regulating BNIP3‑mediated autophagy. International journal of oncology 21 34779489
2006 Molecular cloning of proteasome activator PA28-beta subunit of large yellow croaker (Pseudosciana crocea) and its coordinated up-regulation with MHC class I alpha-chain and beta 2-microglobulin in poly I:C-treated fish. Molecular immunology 20 16901544
1999 A second gene encoding the mouse proteasome activator PA28beta subunit is part of a LINE1 element and is driven by a LINE1 promoter. Journal of molecular biology 18 10222192
2017 Identification of PA28β as a potential novel biomarker in human esophageal squamous cell carcinoma. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 16 29020885
2013 N-α-acetyltransferase 10 protein is a negative regulator of 28S proteasome through interaction with PA28β. FEBS letters 16 23624078
2010 Potential roles for PA28beta in gastric adenocarcinoma development and diagnosis. Journal of cancer research and clinical oncology 14 20140627
2016 Proteasome Activators, PA28α and PA28β, Govern Development of Microvascular Injury in Diabetic Nephropathy and Retinopathy. International journal of nephrology 11 27830089
2003 Cloning and sequence analysis of cDNA for the proteasome activator PA28-beta subunit of flounder (Paralichthys olivaceus). Molecular immunology 11 14597164
2000 PA28alphabeta double and PA28beta single transfectant mouse B8 cell lines reveal enhanced presentation of a mouse cytomegalovirus (MCMV) pp89 MHC class I epitope. Molecular immunology 10 10781831
2004 Sequence characterization, polymorphism and chromosomal localizations of the porcine PSME1 and PSME2 genes. Animal genetics 9 15373739
2022 PSME2 identifies immune-hot tumors in breast cancer and associates with well therapeutic response to immunotherapy. Frontiers in genetics 7 36583022
2013 Genomic structural characterization and transcriptional expression analysis of proteasome activator PA28α and PA28β subunits from Oplegnathus fasciatus. Fish & shellfish immunology 4 23916540
2023 YWHAH, a member of 14-3-3 family proteins, and PSME2, the proteasome activator subunit 2, are key host factors of Japanese encephalitis virus infection. BMC medical genomics 2 37430323
2025 PSME2 promotes malignant progression through autophagy modulation via IL-6/STAT3 signaling pathway in esophageal squamous cell carcinoma. Life sciences 1 40404117
2025 Immunoproteasome components LMP2, PSME1, and PSME2 as novel tissue biomarkers predicting response and survival in neoadjuvant chemoimmunotherapy for resectable NSCLC. Frontiers in immunology 1 41035633
2025 PSME2 exacerbates ulcerative colitis by disrupting intestinal barrier function and promoting autophagy-dependent inflammation. Open life sciences 0 41211066