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PSMA2

Proteasome subunit alpha type-2 · UniProt P25787

Length
234 aa
Mass
25.9 kDa
Annotated
2026-06-10
11 papers in source corpus 11 papers cited in narrative 11 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PSMA2 is a structural subunit of the 20S proteasome core particle whose dosage tunes cellular proteasome capacity and broad proteostasis: knockdown reshapes a network of proteins governing immune response, cytokine signaling, autophagy, and the unfolded protein response (PMID:36481484), while overexpression raises bulk proteasome activity and induces the immunoproteasome activator subunits PSME1/2/3 (PMID:41475191). Through this proteolytic control PSMA2 acts as a host factor in viral infection with context-dependent direction — it is required for influenza A virus maturation and is exploited by IAV to suppress NRF2 nuclear translocation and the oxidative-stress response (PMID:35019712), yet it restricts Zika virus replication in astrocytic cells (PMID:36680137) and restrains PRRSV, which counters this defense by driving autophagy-dependent degradation of PSMA2 via its Nsp12 protein (PMID:41475191). In cancer, PSMA2 promotes proliferation and migration: it drives glioma growth through an EMT program with cadherin- and adhesion-molecule-binding partners (PMID:38574629), promotes cervical cancer proliferation downstream of GLP-1R/NF-κB signaling (PMID:33684886), and suppresses mitophagy to confer chemo- and radioresistance in oral squamous cell carcinoma (PMID:39794329). PSMA2 expression is held in check by miR-132, which binds its transcript directly to limit colorectal cancer proliferation (PMID:33537240). The small molecule corynoline binds PSMA2 directly to exert anti-fibrotic effects through NF-κB signaling in pancreatic stellate cells (PMID:39145797).

Mechanistic history

Synthesis pass · year-by-year structured walk · 4 steps
  1. 2021 Medium

    Established PSMA2 as a pro-proliferative effector in cancer and placed it downstream of upstream regulators, answering whether a proteasome subunit can act as a node in oncogenic signaling.

    Evidence shRNA knockdown with in vitro proliferation and xenograft readouts, GLP-1R silencing and Exendin-4 treatment with NF-κB Western blots in cervical cancer; luciferase reporter showing direct miR-132 targeting in CRC

    PMID:33537240 PMID:33684886

    Open questions at the time
    • Does not resolve whether the proliferative effect depends on PSMA2's proteasome activity or a moonlighting function
    • Mechanistic link between GLP-1R, PSMA2 levels, and NF-κB not biochemically defined
  2. 2022 Medium

    Defined PSMA2 as a broad proteostasis and immune-signaling regulator and revealed opposing roles across viruses, reframing it as a context-dependent host factor rather than a passive structural subunit.

    Evidence siRNA knockdown in A549 cells with SOMAScan proteome-wide profiling, IAV titer/NRF2 translocation/ROS assays, and ZIKV titer/protein-synthesis assays in U251 cells

    PMID:35019712 PMID:36481484 PMID:36680137

    Open questions at the time
    • The molecular basis of the IAV-versus-ZIKV directional difference is unexplained
    • Whether NRF2 suppression is a direct proteasome-dependent event is not established
    • Single-lab, single-method (knockdown) for each phenotype
  3. 2024 Medium

    Identified direct small-molecule and protein interactions of PSMA2, advancing it from a phenotypic correlate to a druggable molecular target and EMT driver.

    Evidence Lip-SMap and DARTS showing direct corynoline binding plus siRNA epistasis in pancreatic stellate cells; Co-IP mass spectrometry, EMT-marker Western blots, and xenograft loss-of-function in glioma

    PMID:38574629 PMID:39145797

    Open questions at the time
    • Corynoline binding site on PSMA2 and its effect on proteasome activity not mapped
    • EMT partners identified by Co-IP MS not individually validated
    • Connection between PSMA2's proteasome role and EMT induction unresolved
  4. 2025 Medium

    Linked PSMA2 to mitophagy, HSP90/AR signaling, and proteasome activity control, extending its mechanistic reach into therapy resistance and antiviral defense.

    Evidence Knockdown/overexpression with mitophagy inducers and xenografts in OSCC; HSP90 turnover, AR activity, and enzalutamide re-sensitization assays in prostate cancer (preprint); proteasome activity, PSME1/2/3 induction, and Nsp12-mediated autophagic degradation assays for PRRSV restriction

    PMID:39794329 PMID:41394666 PMID:41475191

    Open questions at the time
    • How a proteasome subunit suppresses mitophagy mechanistically is undefined
    • HSP90/AR finding is from a preprint not yet peer-reviewed
    • Whether PSME1/2/3 induction is transcriptionally direct is not shown

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unknown how PSMA2 dosage and its 20S-core function are mechanistically partitioned among its many context-dependent roles (antiviral restriction, viral maturation, EMT, mitophagy, AR signaling).
  • No structural or biochemical account of how PSMA2 perturbation selectively rewires distinct pathways
  • No demonstration that the opposing viral phenotypes share a common proteasome-dependent mechanism
  • Disease causality of the PAN3-PSMA2 fusion not functionally tested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 2
Pathway
R-HSA-168256 Immune System 3 R-HSA-392499 Metabolism of proteins 2
Partners
CORYNOLINEHSP90PRRSV NSP12
Complex memberships
20S proteasome core particle

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2022 PSMA2 is required for influenza A virus (IAV) maturation: PSMA2 knockdown in A549 cells significantly reduced extracellular progeny IAV titers without affecting intracellular viral protein translation or viral RNA transcription, indicating PSMA2 acts at a post-transcriptional/maturation stage. Additionally, PSMA2 is required for NRF2-mediated ROS neutralization; IAV uses PSMA2 to suppress NRF2 nuclear translocation and dampen the oxidative stress response, thereby escaping viral clearance. siRNA knockdown in A549 cells, SomaScan proteomics (1307 proteins), NRF2 nuclear translocation assay, ROS measurement Journal of virology Medium 35019712
2022 PSMA2 knockdown in human lung epithelial A549 cells dysregulates 52 proteins involved in immune response, cytokine signaling, autophagy, unfolded protein response, and cancer-related signaling, establishing PSMA2 as a broad regulator of cellular proteostasis and immune signaling. siRNA knockdown, SOMAScan aptamer-based multiplexed proteomics measuring >1300 proteins Biochimica et biophysica acta. Molecular basis of disease Medium 36481484
2022 PSMA2 acts as a restriction factor for Zika virus (ZIKV) replication in astrocytic cells: siRNA-mediated knockdown of PSMA2 increased ZIKV titers and viral protein synthesis in U251 glioblastoma cells. siRNA knockdown, ZIKV titer measurement, viral protein synthesis assay Viruses Medium 36680137
2024 Corynoline binds directly to PSMA2 (identified by Lip-SMap and validated by DARTS), and siRNA knockdown of PSMA2 abrogates the anti-fibrotic effect of corynoline in pancreatic stellate cells, placing PSMA2 in the NF-κB signaling pathway as the molecular target mediating corynoline's inhibition of pancreatic fibrosis. Lip-SMap (limited proteolysis–small molecule mapping), DARTS (drug affinity responsive target stability), siRNA knockdown, in vitro collagen synthesis assay, NF-κB pathway analysis Journal of gastroenterology Medium 39145797
2024 PSMA2 promotes glioma cell proliferation and migration via the epithelial-mesenchymal transition (EMT) pathway. Co-IP mass spectrometry identified PSMA2-binding proteins enriched in cell adhesion molecule binding and cadherin binding; PSMA2 knockdown suppressed EMT markers as confirmed by Western blot, and inhibited tumor growth in vivo. Co-immunoprecipitation mass spectrometry (Co-IP MS), CCK-8/colony formation/transwell assays, Western blot for EMT markers, xenograft mouse model Pathology, research and practice Medium 38574629
2021 PSMA2 promotes cervical cancer cell proliferation; psma2-shRNA knockdown decreased cell proliferation in vitro and reduced tumor volume and Ki67 expression in vivo. GLP-1R silencing decreased PSMA2 expression, and Exendin-4 decreased PSMA2 expression and attenuated phospho-p65 and phospho-IκB in the NF-κB pathway. shRNA knockdown, in vitro proliferation assay, xenograft mouse model, Ki67 immunostaining, siRNA silencing of GLP-1R, Western blot for NF-κB pathway components EBioMedicine Medium 33684886
2021 PSMA2 is a direct target of miR-132: luciferase reporter assay confirmed that miR-132 directly regulates PSMA2 expression, and miR-132 mimic reduced CRC cell proliferation, establishing PSMA2 as a downstream effector of miR-132 in colorectal cancer. Luciferase reporter assay, miRNA mimic transfection, loss-of-function experiments in CRC cell lines Frontiers in oncology Medium 33537240
2025 PSMA2 regulates cell cycle progression, mitochondrial dysfunction, and mitophagy in OSCC cells, contributing to chemo- and radioresistance. PSMA2 overexpression in a xenograft model was countered by mitophagy inducers, demonstrating that PSMA2-mediated suppression of mitophagy is the mechanistic basis of treatment resistance. PSMA2 knockdown/overexpression, cell cycle analysis, mitochondrial function assays, xenograft mouse model with mitophagy inducer treatment Cell death discovery Medium 39794329
2025 PSMA2 overexpression accelerates HSP90 turnover and hypersensitizes the androgen receptor (AR) to residual androgen under castration conditions, driving AR nuclear activity and conferring enzalutamide resistance in prostate cancer. Conversely, PSMA2 silencing stabilizes HSP90, desensitizes cells to androgen, and re-sensitizes resistant cells to enzalutamide. PSMA2 also promotes transcriptional and phenotypic neuroendocrine lineage conversion (tNEPC). PSMA2 overexpression and siRNA knockdown, HSP90 stability assay, AR nuclear translocation/activity assay, androgen sensitivity assay, enzalutamide resistance/re-sensitization assay, neuroendocrine marker analysis bioRxivpreprint Medium 41394666
2025 PRRSV nonstructural protein Nsp12 promotes autophagy-dependent degradation of PSMA2 protein to suppress host proteasome activity. PSMA2 overexpression enhances cellular proteasome activity and upregulates immunoproteasome activator subunits PSME1, PSME2, and PSME3, while PSMA2 silencing reduces proteasome activity and promotes PRRSV replication, establishing PSMA2 as an antiviral host restriction factor. Overexpression and siRNA knockdown, proteasome activity assay, PSME1/2/3 transcription analysis, Nsp12 interaction screen, autophagy inhibitor experiments Veterinary microbiology Medium 41475191
2018 A t(7;13)(p14;q12) chromosomal translocation in MDS/AML generates an out-of-frame PAN3-PSMA2 fusion transcript, disrupting the PSMA2 reading frame and implicating loss of normal PSMA2 function (as part of the 20S proteasome) in disease pathogenesis. RNA sequencing, RT-PCR, Sanger sequencing, interphase FISH Experimental hematology & oncology Low 29560286

Source papers

Stage 0 corpus · 11 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2021 Increased co-expression of PSMA2 and GLP-1 receptor in cervical cancer models in type 2 diabetes attenuated by Exendin-4: A translational case-control study. EBioMedicine 28 33684886
2022 PSMA2 knockdown impacts expression of proteins involved in immune and cellular stress responses in human lung cells. Biochimica et biophysica acta. Molecular basis of disease 15 36481484
2021 Comprehensively Analyzed Macrophage-Regulated Genes Indicate That PSMA2 Promotes Colorectal Cancer Progression. Frontiers in oncology 15 33537240
2022 Influenza A Virus Uses PSMA2 for Downregulation of the NRF2-Mediated Oxidative Stress Response. Journal of virology 14 35019712
2018 PAN3-PSMA2 fusion resulting from a novel t(7;13)(p14;q12) chromosome translocation in a myelodysplastic syndrome that evolved into acute myeloid leukemia. Experimental hematology & oncology 11 29560286
2024 Corynoline protects chronic pancreatitis via binding to PSMA2 and alleviating pancreatic fibrosis. Journal of gastroenterology 9 39145797
2024 PSMA2 promotes glioma proliferation and migration via EMT. Pathology, research and practice 6 38574629
2022 HLA-A, HSPA5, IGFBP5 and PSMA2 Are Restriction Factors for Zika Virus Growth in Astrocytic Cells. Viruses 6 36680137
2025 PSMA2 promotes chemo- and radioresistance of oral squamous cell carcinoma by modulating mitophagy pathway. Cell death discovery 5 39794329
2025 Therapy-induced PSMA2 Sensitizes Prostate Cancer Cells to Residual Androgen and Promotes Neuroendocrine Lineage Transformation. bioRxiv : the preprint server for biology 0 41394666
2025 PRRSV Nsp12 targets PSMA2 to suppress host proteasome activity and promote viral survival. Veterinary microbiology 0 41475191

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