Affinage

PSMG2

Proteasome assembly chaperone 2 · UniProt Q969U7

Length
264 aa
Mass
29.4 kDa
Annotated
2026-06-10
22 papers in source corpus 7 papers cited in narrative 7 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PSMG2 (CLAST3/HCCA3) is a proteasome assembly chaperone that heterodimerizes with PSMG1 to drive maturation of the 20S proteasome (PMID:40303289). Loss of PSMG2 impairs proteasomal activity and causes accumulation of polyubiquitinated proteins, which triggers ER stress and engages autophagy and apoptosis as compensatory responses (PMID:40303289). This proteasome-autophagy balance governed by PSMG2 has downstream signaling consequences: PSMG2 knockdown activates autophagy-mediated degradation of PDPK1, sensitizing triple-negative breast cancer cells to MEK inhibition through the PDPK1-AKT axis, an effect reversed by autophagy blockade (PMID:36099919). PSMG2 expression is transcriptionally maintained by the NFE2L1/NFE2L3 axis, and its depletion impairs basal proteasome activity and reduces resistance to proteasome inhibitors (PMID:32366381). An earlier characterization linked PSMG2 to cell cycle progression, with overexpression causing polyploidy and mitotic spindle checkpoint interference and knockdown reducing G2/M cells and increasing apoptosis (PMID:12147697). Loss-of-function PSMG2 mutations are associated with proteasome-associated autoinflammatory syndrome (PRAAS) bearing a type I interferon signature (PMID:31827472).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2001 Low

    Established PSMG2/HCCA3 as a distinct gene by cloning it from a hepatocellular carcinoma differential-display screen, providing the molecular entity and its tissue expression profile before any function was known.

    Evidence mRNA differential display PCR, cDNA library screening, and Northern blot across human tissues

    PMID:11854909

    Open questions at the time
    • No functional or mechanistic experiment
    • Differential expression in HCC does not establish a causal role
    • Subcellular localization and molecular activity undefined
  2. 2002 Medium

    First functional readout linked PSMG2/CLAST3 to cell cycle control, showing it localizes to nuclear foci and that altering its level perturbs mitotic progression and viability.

    Evidence Immunofluorescence, forced overexpression with nocodazole, and antisense knockdown with cell cycle analysis

    PMID:12147697

    Open questions at the time
    • Mechanistic link between PSMG2 and the spindle checkpoint not defined
    • Predates the proteasome-chaperone model and is not reconciled with it
    • No molecular partners identified
  3. 2020 Medium

    Defined the upstream transcriptional control of PSMG2, placing it under the NFE2L1/NFE2L3 axis that maintains basal proteasome capacity and drug resistance.

    Evidence Double siRNA knockdown of NFE2L1/NFE2L3 with proteasome activity assays and bortezomib resistance readouts

    PMID:32366381

    Open questions at the time
    • PSMG2 is one of seven co-regulated genes, limiting specificity
    • Direct promoter binding not demonstrated
    • Contribution of PSMG2 alone to the proteasome phenotype not isolated
  4. 2021 Low

    Connected PSMG2 to neurodegeneration-associated proteostasis by identifying it as an interactor of cytoplasmic mutant TDP-43 in a context of proteasomal impairment.

    Evidence Immunoprecipitation and mass spectrometry from a rhesus model expressing mutant TDP-43(M337V)

    PMID:34363810

    Open questions at the time
    • Single Co-IP/MS without reciprocal validation or mutagenesis
    • Functional consequence for PSMG2 specifically not established
    • Direct versus indirect interaction unresolved
  5. 2022 High

    Positioned PSMG2 upstream of a proteasome-autophagy balance that controls PDPK1-AKT signaling, revealing how proteasome assembly failure reshapes oncogenic signaling and drug response.

    Evidence Genome-wide CRISPR-Cas9 screen, knockdown, autophagy-inhibitor rescue, proteasome assays, and xenograft model in TNBC

    PMID:36099919

    Open questions at the time
    • Mechanism by which autophagy selectively targets PDPK1 not defined
    • Generalizability beyond TNBC and MEK-inhibitor context unclear
    • Direct biochemical demonstration of PSMG2 in proteasome assembly not shown here
  6. 2025 Medium

    Provided the core mechanistic model that PSMG2 heterodimerizes with PSMG1 to assemble the 20S proteasome, linking its loss to polyubiquitin accumulation, ER stress, and compensatory autophagy/apoptosis.

    Evidence Knockdown in HNSCC cells with polyubiquitin, ER stress, autophagy/apoptosis, and stemness assays in vitro and in vivo

    PMID:40303289

    Open questions at the time
    • Structural details of the PSMG1-PSMG2 heterodimer not resolved
    • Direct reconstitution of assembly chaperone activity not shown
    • Single-lab study

Open questions

Synthesis pass · forward-looking unresolved questions
  • How PSMG2's earlier cell-cycle/spindle-checkpoint phenotype mechanistically relates to its role as a 20S proteasome assembly chaperone remains unresolved.
  • No structural model of PSMG1-PSMG2 acting on 20S intermediates
  • Direct biochemical demonstration of chaperone-mediated assembly in human cells absent
  • Reconciliation of nuclear-foci localization with cytoplasmic proteasome assembly function unaddressed

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005634 nucleus 1
Pathway
R-HSA-392499 Metabolism of proteins 2 R-HSA-9612973 Autophagy 2
Partners
PSMG1TDP-43
Complex memberships
PSMG1-PSMG2 proteasome assembly chaperone heterodimer

Evidence

Reading pass · 7 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 CLAST3 (PSMG2) is a cell cycle-regulated protein that localizes to discrete nuclear foci; forced overexpression induces growth retardation, polyploidy, and multinucleated cells by interfering with the mitotic spindle checkpoint, while antisense-mediated knockdown decreases G2/M cells and increases apoptosis. Immunofluorescence localization, forced overexpression with nocodazole treatment, antisense oligonucleotide knockdown with cell cycle analysis The Journal of biological chemistry Medium 12147697
2022 PSMG2 knockdown impairs proteasome function, which in turn activates autophagy-mediated PDPK1 degradation, significantly enhancing MEK inhibitor (AZD6244)-induced tumor growth inhibition in TNBC cells; the autophagy inhibitor chloroquine partially reverses PDPK1 degradation and the growth inhibition phenotype, placing PSMG2 upstream of proteasome-autophagy balance and PDPK1-AKT negative feedback signaling. Genome-wide CRISPR-Cas9 screen, PSMG2 knockdown, autophagy inhibitor rescue, proteasome activity assays, xenograft mouse model Cell reports. Medicine High 36099919
2025 PSMG2 forms a heterodimer with PSMG1 and promotes assembly of the 20S proteasome; knockdown of PSMG2 in HNSCC cells causes accumulation of polyubiquitinated proteins, triggers ER stress, activates autophagy and apoptosis as compensatory mechanisms, and reduces stemness and dedifferentiation properties in vitro and in vivo. PSMG2 knockdown in cancer cell lines, polyubiquitinated protein accumulation assay, ER stress markers, autophagy/apoptosis assays, in vitro and in vivo proliferation/stemness assays International journal of biological sciences Medium 40303289
2021 Cytoplasmic mutant TDP-43 interacts with proteasome assembly protein PSMG2 (and PSD13) as identified by immunoprecipitation and mass spectrometry, and this interaction is associated with impairment of proteasomal activity. Immunoprecipitation and mass spectrometry from rhesus monkey model expressing mutant TDP-43(M337V) Experimental neurology Low 34363810
2020 NFE2L1 and NFE2L3 double knockdown significantly reduces basal expression of PSMG2 (along with six other proteasome-related genes), impairs basal proteasome activity in cancer cells, and reduces resistance to the proteasome inhibitor bortezomib, placing PSMG2 expression under transcriptional control of the NFE2L1/NFE2L3 axis. Double siRNA knockdown of NFE2L1 and NFE2L3, proteasome activity assay, bortezomib resistance assay, gene expression analysis Molecular and cellular biology Medium 32366381
2001 HCCA3 (PSMG2) was cloned as a novel full-length cDNA identified by differential display PCR between hepatocellular carcinoma and surrounding liver tissue; it is widely distributed in human normal tissues with high expression in lung, brain, and colon and low expression in liver. mRNA differential display PCR, cDNA library screening, Northern blot World journal of gastroenterology Low 11854909
2019 PSMG2 is identified as a proteasome assembly factor whose loss-of-function mutations cause PRAAS (proteasome-associated autoinflammatory syndrome) with a type I interferon signature, placing PSMG2 in the pathway of proteasome assembly alongside PSMB8, PSMB9, PSMB7, PSMA3, and POMP; disruption leads to accumulation of ubiquitinated proteins. Review synthesizing genetic and functional data from PRAAS patient mutations and cellular studies Frontiers in immunology Low 31827472

Source papers

Stage 0 corpus · 22 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2020 Distinct interferon signatures and cytokine patterns define additional systemic autoinflammatory diseases. The Journal of clinical investigation 190 31874111
2013 Extended survival and reduced risk of AML progression in erythroid-responsive lenalidomide-treated patients with lower-risk del(5q) MDS. Leukemia 79 24150217
2019 Contribution of the Unfolded Protein Response (UPR) to the Pathogenesis of Proteasome-Associated Autoinflammatory Syndromes (PRAAS). Frontiers in immunology 64 31827472
2012 Lenalidomide does not increase AML progression risk in RBC transfusion-dependent patients with Low- or Intermediate-1-risk MDS with del(5q): a comparative analysis. Leukemia 64 23257782
2018 Poliovirus induces autophagic signaling independent of the ULK1 complex. Autophagy 49 29929428
2020 NFE2L1 and NFE2L3 Complementarily Maintain Basal Proteasome Activity in Cancer Cells through CPEB3-Mediated Translational Repression. Molecular and cellular biology 42 32366381
2006 Lenalidomide: targeted anemia therapy for myelodysplastic syndromes. Cancer control : journal of the Moffitt Cancer Center 28 17242661
2022 PSMG2-controlled proteasome-autophagy balance mediates the tolerance for MEK-targeted therapy in triple-negative breast cancer. Cell reports. Medicine 24 36099919
2021 Cytoplasmic TDP-43 impairs the activity of the ubiquitin-proteasome system. Experimental neurology 23 34363810
2015 Short- and long-term benefits of lenalidomide treatment in patients with lower-risk del(5q) myelodysplastic syndromes. Annals of oncology : official journal of the European Society for Medical Oncology 21 26504152
2002 Growth retardation, polyploidy, and multinucleation induced by Clast3, a novel cell cycle-regulated protein. The Journal of biological chemistry 16 12147697
2024 Evaluating the association between placenta DNA methylation and cognitive functions in the offspring. Translational psychiatry 15 39304652
2019 Expressions of Shell Matrix Protein Genes in the Pearl Sac and Its Correlation with Pearl Weight in the First 6 Months of Pearl Formation in Hyriopsis cumingii. Marine biotechnology (New York, N.Y.) 14 30659442
2012 Acquiring transgenic tobacco plants with insect resistance and glyphosate tolerance by fusion gene transformation. Plant cell reports 13 22777591
2007 Immunomodulatory drugs in the treatment of myelodysplastic syndromes. Current opinion in oncology 11 17906467
2021 Development of an exosomal gene signature to detect residual disease in dogs with osteosarcoma using a novel xenograft platform and machine learning. Laboratory investigation; a journal of technical methods and pathology 10 34489559
2023 Identification of candidate mitochondrial inheritance determinants using the mammalian cell-free system. eLife 8 37470242
2013 Lenalidomide: a review of its use in patients with transfusion-dependent anaemia due to low- or intermediate-1-risk myelodysplastic syndrome associated with 5q chromosome deletion. Drugs 8 23824699
2009 Lenalidomide--a transforming therapeutic agent in myelodysplastic syndromes. Clinical lymphoma & myeloma 8 19778857
2001 Expression of liver cancer associated gene HCCA3. World journal of gastroenterology 7 11854909
2017 Identification, structural characterization and expression analysis of a novel carbonic anhydrase from freshwater mussel Hyriopsis cumingii. Gene 6 28866087
2025 PSMG2 role in tumorigenesis and stemness mediated by protein accumulation, reticulum stress and autophagy. International journal of biological sciences 2 40303289

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