Affinage

PIAS2

E3 SUMO-protein ligase PIAS2 · UniProt O75928

Length
621 aa
Mass
68.2 kDa
Annotated
2026-06-10
12 papers in source corpus 8 papers cited in narrative 8 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/6 claims corpus-supported (83%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PIAS2 is a SUMO E3 ligase and context-dependent transcriptional co-regulator that acts at the interface of nuclear receptor signaling, innate immune transcription, and protein stability control (PMID:32249212, PMID:11117529). As a SUMO ligase it conjugates SUMO1/2/3 onto substrate transcription factors and receptors: it modifies ZFHX3 primarily at Lys-2806, which blocks ZFHX3 ubiquitination and proteasomal degradation to enhance its stability and support cell proliferation and tumor growth (PMID:32249212), and, recruited as a scaffold by TRAF2 in IL-17 signaling, it SUMOylates EPHA5 to similarly protect it from ubiquitin-mediated turnover and promote proliferation and invasion (PMID:37481078). In nuclear receptor signaling PIAS2 directly binds the androgen receptor and represses its transcriptional activity, a repression relieved when DJ-1 competitively displaces AR from PIAS2, while the same protein differentially enhances glucocorticoid receptor-dependent transcription (PMID:11477070, PMID:11117529). Its co-regulatory output is tunable by upstream kinase state: p38 MAPK-dependent phosphorylation switches PIAS2 into a corepressor of Elk-1 coupled to SUMO1 modification of Elk-1 (PMID:30783905). PIAS2 also exerts SUMO-independent functions, including inhibition of IRF7 to repress RIG-I-driven IFN-β promoter activation through its C-terminal region (PMID:32151676), and, in neurons, suppression of mitophagy and inactivation of ERK1/2-P53 signaling downstream of JAK-STAT2, driving mitochondrial senescence, oxidative stress, and dopaminergic neuron loss (PMID:34234281). It physically associates with RACK1 via its PINIT and RLD domains (PMID:22210188).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2000 Medium

    Established that PIAS2 is not a uniform coactivator but a differential modulator of steroid receptor transcription, repressing AR while enhancing GR, distinguishing it functionally from other PIAS family members.

    Evidence Cotransfection luciferase reporter assays on natural and minimal promoters comparing four PIAS proteins in multiple cell types

    PMID:11117529

    Open questions at the time
    • No in vitro reconstitution or active-site mutagenesis to link the effect to SUMO ligase activity
    • Mechanism of opposite effects on AR vs GR not resolved
    • Direct binding to each receptor not mapped here
  2. 2001 High

    Defined a regulatory switch for AR activity by showing PIAS2 directly binds and represses AR and that DJ-1 competitively displaces AR from PIAS2 to restore AR transcription.

    Evidence Yeast two-hybrid, reciprocal Co-IP in vitro and in 293T cells, colocalization, and ARE-luciferase reporter with a DJ-1 K130R mutagenesis control in CV1 cells

    PMID:11477070

    Open questions at the time
    • Whether repression requires PIAS2 SUMO ligase activity not tested
    • Physiological setting and endogenous stoichiometry of the AR-PIAS2-DJ-1 competition undefined
  3. 2011 Medium

    Identified RACK1 as a direct PIAS2 partner and mapped the interaction to the PINIT and RLD domains of PIAS2 and WD40 repeats 5-7 of RACK1, providing a structural interface but no assigned function.

    Evidence Yeast two-hybrid, Co-IP deletion mapping, and immunofluorescence colocalization

    PMID:22210188

    Open questions at the time
    • Functional consequence of the RACK1-PIAS2 interaction not established
    • Whether RACK1 modulates PIAS2 SUMO ligase activity unknown
  4. 2019 Medium

    Showed that upstream kinase state controls PIAS2 co-regulatory output: p38 MAPK-dependent phosphorylation converts PIAS2 into an Elk-1 corepressor associated with SUMO1 modification of Elk-1.

    Evidence p38 inhibitor (SB203580) treatment, Elk-1 luciferase reporter and target-gene qPCR, and PIAS2 phosphorylation western blots in heat-stressed HeLa cells

    PMID:30783905

    Open questions at the time
    • The p38 phosphorylation site on PIAS2 was not mutated to prove causality
    • Direct SUMOylation of Elk-1 by PIAS2 not reconstituted
    • ERK-state coactivator switch inferred rather than directly demonstrated
  5. 2020 High

    Demonstrated bona fide SUMO E3 ligase activity of PIAS2 toward ZFHX3 at Lys-2806 and established that this SUMOylation stabilizes the substrate by antagonizing ubiquitin-proteasomal degradation, linking PIAS2 to proliferation and tumor growth.

    Evidence Co-IP, SUMOylation assays, Lys-2806 mutagenesis, ubiquitination and proteasome-inhibitor experiments, and MDA-MB-231 xenografts

    PMID:32249212

    Open questions at the time
    • Whether SUMOylation directly occludes ubiquitin sites or recruits stabilizing factors unresolved
    • In vitro reconstitution with purified components not reported
  6. 2020 Medium

    Revealed a SUMO-ligase-independent immune-regulatory function by showing the duck PIAS2 ortholog binds and inhibits IRF7 to repress RIG-I-induced IFN-β promoter activation via its C-terminal region.

    Evidence Overexpression with IFN-β luciferase reporter, Co-IP with duck IRF7, and domain-deletion plus ligase-dead mutant analysis

    PMID:32151676

    Open questions at the time
    • Demonstrated in duck ortholog, not human PIAS2
    • Endogenous IRF7 inhibition and physiological IFN response not tested
    • Mechanism of C-terminal IRF7 inhibition undefined
  7. 2021 Medium

    Placed PIAS2 as a downstream effector of JAK-STAT2 signaling controlling neuronal mitochondrial homeostasis, showing its overexpression blocks mitophagy and inactivates ERK1/2-P53 to drive oxidative stress and dopaminergic neuron loss, reversible by knockdown.

    Evidence In vivo viral overexpression and knockdown in mouse and Ifnb-/- mouse neurons, behavioral tests, mitophagy assays, oxidative-stress and pERK1/2/pP53 western/immunostaining

    PMID:34234281

    Open questions at the time
    • No in vitro reconstitution of a PIAS2-ERK1/2 interaction
    • Whether the neuronal effect requires SUMO ligase activity unknown
    • Direct molecular target of PIAS2 in this pathway not identified
  8. 2023 Medium

    Generalized the SUMO-mediated stabilization mechanism to a second substrate by showing TRAF2 recruits PIAS2 to SUMOylate EPHA5, blocking its ubiquitination and degradation to promote melanoma proliferation and invasion in IL-17 signaling.

    Evidence Co-IP, siRNA knockdown of PIAS2/TRAF2/ELAVL1/EPHA5, SUMOylation and ubiquitination western blots, and proliferation/invasion assays

    PMID:37481078

    Open questions at the time
    • No in vitro reconstitution of PIAS2 SUMO ligase activity toward EPHA5
    • EPHA5 SUMO acceptor lysine not mapped
    • Role of the TRAF2 scaffold step mechanistically undefined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How PIAS2 selects between SUMO-ligase-dependent (ZFHX3, EPHA5) and SUMO-independent (IRF7, AR repression, neuronal ERK1/2) modes, and what determines its substrate and partner specificity, remains unresolved.
  • No unifying structural or biochemical determinant of mode-switching identified
  • Most substrates lack in vitro reconstitution with purified components
  • Endogenous regulation and tissue context of competing functions undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 3 GO:0016740 transferase activity 2 GO:0098772 molecular function regulator activity 2 GO:0140096 catalytic activity, acting on a protein 2
Localization
GO:0005634 nucleus 2
Pathway
R-HSA-74160 Gene expression (Transcription) 3 R-HSA-162582 Signal Transduction 2 R-HSA-168256 Immune System 2 R-HSA-392499 Metabolism of proteins 2
Partners
ARDJ-1ELK1EPHA5IRF7RACK1TRAF2ZFHX3

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 PIASx alpha (PIAS2) directly binds the androgen receptor (AR)-binding region of PIASx alpha and inhibits AR transcriptional activity in a dose-dependent manner. DJ-1 competes with AR for binding to PIASx alpha, disrupting the AR–PIASx alpha complex and thereby restoring AR transcription activity. A DJ-1 mutant (K130R) fails to restore AR activity, demonstrating the specificity of this competition. Yeast two-hybrid screening, in vitro co-immunoprecipitation, co-immunoprecipitation in human 293T cells, co-localization by fluorescence microscopy, androgen-responsive element-luciferase reporter assay in CV1 cells The Journal of biological chemistry High 11477070
2000 ARIP3/PIASx alpha (PIAS2) differentially modulates steroid receptor-dependent transcription: it represses AR activity on a natural probasin promoter but enhances glucocorticoid receptor-dependent transcription more efficiently than other PIAS family members. Unlike Miz1/PIASx beta and PIAS1, ARIP3 lacks an inherent transcriptional activation function. All PIAS proteins tested have only marginal effects on STAT-mediated transactivation at the same doses. Cotransfection with luciferase reporter constructs driven by natural (probasin) or minimal promoters in multiple cell types; comparison of four PIAS family members Molecular endocrinology (Baltimore, Md.) Medium 11117529
2021 Neuronal overexpression of PIAS2 blocks mitophagy and inactivates ERK1/2-P53 signaling, leading to accumulation of senescent mitochondria, oxidative stress (elevated oxDJ1 and 8OHdG), phospho-α-synuclein accumulation, and dopaminergic neuron loss. Conversely, PIAS2 knockdown in Ifnb−/− mice rescues these phenotypes and restores mitochondrial homeostasis and pERK1/2-pP53 signaling. PIAS2 is identified as a downstream effector of the JAK-STAT2 pathway that also controls neurite outgrowth and neuronal survival. In vivo neuronal overexpression via stereotaxic viral injection in mice, PIAS2 knockdown in Ifnb−/− mice, behavioral testing, immunostaining for pα-synuclein and oxidative stress markers, mitophagy assays, western blotting for ERK1/2 and P53 phosphorylation Molecular psychiatry Medium 34234281
2020 PIAS2 acts as a SUMO E3 ligase for the transcription factor ZFHX3, conjugating SUMO1, SUMO2, and SUMO3 primarily at Lys-2806. SUMOylation at this site enhances ZFHX3 protein stability by interfering with ubiquitination and proteasomal degradation, and enables ZFHX3-mediated cell proliferation and xenograft tumor growth. Co-immunoprecipitation, SUMOylation assays, site-directed mutagenesis of Lys-2806, ubiquitination assays, proteasome inhibitor experiments, xenograft tumor growth assays in MDA-MB-231 cells The Journal of biological chemistry High 32249212
2019 In heat-stressed HeLa cells, PIAS2 is phosphorylated via the p38 MAPK pathway. Phosphorylated PIAS2 acts as a corepressor of the transcription factor Elk-1 (rather than a coactivator, which is the ERK-activation state). p38 MAPK pathway-dependent phosphorylation of PIAS2 correlates with SUMO1-modification of Elk-1 and downregulation of Elk-1 transcriptional activity. MAPK-pathway-specific inhibitors (SB203580), luciferase reporter assays for Elk-1 activity, qPCR of Elk-1 target genes, western blotting for PIAS2 phosphorylation in HeLa cells Cell stress & chaperones Medium 30783905
2011 RACK1 was identified as a direct binding partner of PIAS2. The interaction requires the 5th–7th WD40 repeats of RACK1 and multiple domains of PIAS2, particularly the PINIT and RLD domains. RACK1 and PIAS2 co-localize in cells. Yeast two-hybrid screening, co-immunoprecipitation, immunofluorescence co-localization, deletion mapping by co-immunoprecipitation FEBS letters Medium 22210188
2023 In the IL-17 signaling cascade in melanoma cells, TRAF2 recruits PIAS2 as a scaffold, and PIAS2 induces SUMOylation of EPHA5, which suppresses EPHA5 ubiquitination and proteasomal degradation, thereby stabilizing EPHA5 protein and promoting cell proliferation and invasion. Co-immunoprecipitation, siRNA knockdown of PIAS2, TRAF2, ELAVL1, and EPHA5, proliferation and invasion assays, western blotting for SUMOylation and ubiquitination of EPHA5 Biochimica et biophysica acta. Molecular cell research Medium 37481078
2020 Duck PIAS2 (an ortholog of mammalian PIAS2) interacts with and inhibits duck IRF7, repressing IFN-β promoter activation induced by RIG-I signaling. The inhibitory function does not require SUMO E3 ligase activity but depends on the C-terminal portion of the protein. Cloning of duPIAS2, overexpression with IFN-β promoter-luciferase reporter assay, co-immunoprecipitation with duck IRF7, domain-deletion and ligase-dead mutant analysis Developmental and comparative immunology Medium 32151676

Source papers

Stage 0 corpus · 12 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 DJ-1 positively regulates the androgen receptor by impairing the binding of PIASx alpha to the receptor. The Journal of biological chemistry 282 11477070
2000 ARIP3 (androgen receptor-interacting protein 3) and other PIAS (protein inhibitor of activated STAT) proteins differ in their ability to modulate steroid receptor-dependent transcriptional activation. Molecular endocrinology (Baltimore, Md.) 150 11117529
2021 PIAS2-mediated blockade of IFN-β signaling: a basis for sporadic Parkinson disease dementia. Molecular psychiatry 46 34234281
2020 SUMOylation of the transcription factor ZFHX3 at Lys-2806 requires SAE1, UBC9, and PIAS2 and enhances its stability and function in cell proliferation. The Journal of biological chemistry 31 32249212
2022 Curcumin relieved the rheumatoid arthritis progression via modulating the linc00052/miR-126-5p/PIAS2 axis. Bioengineered 15 35473503
2022 Integrative transcriptome analysis reveals TEKT2 and PIAS2 involvement in diabetic nephropathy. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 11 36251411
2023 IL-17 promotes melanoma through TRAF2 as a scaffold protein recruiting PIAS2 and ELAVL1 to induce EPHA5. Biochimica et biophysica acta. Molecular cell research 10 37481078
2020 Duck PIAS2 negatively regulates RIG-I mediated IFN-β production by interacting with IRF7. Developmental and comparative immunology 10 32151676
2019 p38 MAPK pathway-dependent SUMOylation of Elk-1 and phosphorylation of PIAS2 correlate with the downregulation of Elk-1 activity in heat-stressed HeLa cells. Cell stress & chaperones 10 30783905
2011 Interaction of protein inhibitor of activated STAT 2 (PIAS2) with receptor of activated C kinase 1, RACK1. FEBS letters 7 22210188
2020 Duck PIAS2 Promotes H5N1 Avian Influenza Virus Replication Through Its SUMO E3 Ligase Activity. Frontiers in microbiology 5 32595623
2025 Chicken PIAS2 enhances H6N2 avian influenza virus replication by promoting SUMOylation of viral NP. Veterinary research 0 41413919

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