Affinage

PIAS4

E3 SUMO-protein ligase PIAS4 · UniProt Q8N2W9

Length
510 aa
Mass
56.5 kDa
Annotated
2026-04-28
85 papers in source corpus 45 papers cited in narrative 43 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PIAS4 (PIASy) is a SUMO E3 ligase that conjugates SUMO-1, SUMO-2, and SUMO-3 to a broad spectrum of substrates to regulate transcription, DNA damage repair, mitotic chromosome segregation, innate immunity, and metabolic signaling. Its E3 ligase activity requires two C-terminal SUMO-interacting motifs (SIMs) and typically its RING-finger-like (SP-RING) domain, although certain substrates such as YY1 are SUMOylated in a RING-independent manner; PIAS4 also represses transcription through SUMO-independent mechanisms involving HDAC1/HDAC2 recruitment via its RD1 domain and nuclear-matrix sequestration of substrates via its SAP domain (PMID:11731474, PMID:14981544, PMID:18477566, PMID:17353273, PMID:28455449). At DNA double-strand breaks, PIAS4 accumulates via its SAP domain and drives SUMO accrual that is essential for 53BP1, BRCA1, and RNF168 recruitment, ubiquitin-adduct formation, and homologous recombination; on mitotic chromosomes, its N-terminal domain binds the Rod/Zw10 kinetochore complex to direct centromeric SUMOylation of Topoisomerase IIα and PARP1, controlling decatenation and sister chromatid segregation (PMID:20016603, PMID:35007836, PMID:15933717, PMID:20696768, PMID:21079245). PIAS4 protein stability is regulated by TRIM32- and FIEL1 (KIAA0317)-mediated ubiquitination and proteasomal degradation, linking its abundance to stress signaling and TGF-β pathway output (PMID:16816390, PMID:27162139).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2001 High

    Establishing PIAS4 as a bona fide SUMO E3 ligase: the first reconstituted demonstration showed PIAS4 catalyzes LEF1 SUMOylation and represses LEF1 transcription by relocalizing it to nuclear bodies, defining the core enzymatic activity and a functional paradigm for substrate-directed transcriptional regulation.

    Evidence Reconstituted in vitro SUMOylation assay, co-IP, nuclear fractionation, and reporter assays in mammalian cells

    PMID:11731474

    Open questions at the time
    • Structural basis for substrate recognition unknown
    • Whether E3 activity requires SIMs or RING domain not yet tested
  2. 2003 High

    Rapid substrate expansion—SUMOylation of C/EBPα, GATA-2, c-Myb, and Smad3—established PIAS4 as a broad-specificity E3 ligase that generally represses transcription factor activity through SUMOylation and/or HDAC recruitment, with domain requirements varying by substrate.

    Evidence In vitro SUMOylation assays, mutagenesis, reporter gene assays, co-IP, HDAC inhibitor studies across multiple labs

    PMID:12511558 PMID:12631292 PMID:12750312 PMID:12904571

    Open questions at the time
    • No unifying structural model for how PIAS4 selects diverse substrates
    • HDAC-dependent versus SUMO-dependent repression not dissected for most substrates
  3. 2004 High

    Discovery that PIAS4 performs SUMO-independent transcriptional repression of the androgen receptor via HDAC1/HDAC2 recruitment through its RD1 domain demonstrated that PIAS4 functions as a dual-mechanism corepressor—E3 ligase and HDAC scaffold.

    Evidence SUMO-ligase-dead mutant and AR sumoylation-site mutant analysis, HDAC inhibitor treatment, reporter assays

    PMID:14981544

    Open questions at the time
    • Full set of targets repressed via HDAC-dependent, SUMO-independent mechanism not catalogued
    • Whether HDAC and SUMO arms are ever coordinated on a single substrate is unclear
  4. 2004 High

    Demonstration in Xenopus egg extracts that PIAS4 is essential for mitotic chromosomal SUMO-2 conjugation of Topoisomerase IIα and for sister chromatid segregation established a critical non-transcriptional, cell-cycle-specific function.

    Evidence Xenopus egg extract depletion/reconstitution, chromatin-binding assay, functional segregation assay

    PMID:15933717

    Open questions at the time
    • Mammalian validation of mitotic requirement not yet shown
    • Mechanism by which PIAS4 is recruited to mitotic chromosomes undefined
  5. 2006 High

    Multiple parallel advances defined PIAS4's roles in stress signaling (NEMO SUMOylation activating NF-κB upon genotoxic stress), cellular senescence (p53 SUMOylation/Rb-dependent repression), and protein homeostasis (TRIM32-mediated ubiquitination and degradation of PIAS4 itself).

    Evidence siRNA knockdown, in vitro SUMOylation and ubiquitination assays, ko fibroblasts, chromatin IP, RING domain mutagenesis

    PMID:16793547 PMID:16816390 PMID:16906147

    Open questions at the time
    • How TRIM32-PIAS4 axis is regulated beyond UVB/TNFα not explored
    • Whether senescence function is entirely p53/Rb-dependent or involves additional substrates
  6. 2007 High

    Knockout studies in dendritic cells showed PIAS4 restricts NF-κB and STAT1-dependent gene activation in innate immune signaling, and Pias1/Pias4 double-knockout embryonic lethality revealed functional cooperation with PIAS1, establishing non-redundant in vivo roles.

    Evidence Gene-knockout mice, LPS/IFN-γ stimulation, double-knockout embryo analysis

    PMID:17606919

    Open questions at the time
    • Specific substrates mediating embryonic lethality not identified
    • Tissue-specific functions of PIAS4 versus PIAS1 not delineated
  7. 2009 High

    PIAS4 was identified as a key SUMO E3 ligase at DNA double-strand breaks: it accumulates at DSBs via its SAP domain, drives SUMO1/SUMO2/3 modification at damage sites, and is required for productive recruitment of 53BP1, BRCA1, and RNF168, establishing the SUMO-ubiquitin crosstalk paradigm in DNA damage signaling.

    Evidence Laser micro-irradiation, siRNA knockdown, IRIF quantification, clonogenic survival assay

    PMID:20016603

    Open questions at the time
    • Direct DSB substrate(s) of PIAS4 at damage sites not identified at this point
    • Whether PIAS4 is recruited by a specific DNA structure or protein platform unknown
  8. 2010 High

    The mechanism of PIAS4 chromosomal targeting was resolved: its N-terminal domain directly interacts with the Rod/Zw10 kinetochore complex, and this interaction is required for centromeric SUMOylation of both TopoIIα (inhibiting decatenation) and PARP1 (modulating PARylation), explaining how PIAS4 coordinates chromosome segregation.

    Evidence Xenopus egg extract depletion, co-IP, mass spectrometry site identification, in vitro SUMOylation and enzymatic assays, truncation mutagenesis

    PMID:20228053 PMID:20696768 PMID:21079245

    Open questions at the time
    • Whether Rod/Zw10-dependent recruitment is conserved in mammalian mitosis not confirmed
    • How SUMOylation of TopoIIα and PARP1 are temporally coordinated unclear
  9. 2011 High

    PIAS4 was shown to inhibit type I IFN transcription through a SIM-dependent/E3-ligase-independent mechanism, while separately suppressing IFN-stimulated gene expression via an LXXLL motif in its SAP domain, revealing two distinct antiviral regulatory arms.

    Evidence PIAS4-knockout cells, SIM and LXXLL mutagenesis, reporter assays, UBC9 knockdown

    PMID:21199872

    Open questions at the time
    • Direct protein target of SIM-dependent IFN repression not identified
    • In vivo antiviral phenotype of PIAS4 loss not fully characterized at this point
  10. 2013 High

    PIAS4 was linked to metabolic regulation: fasting-induced PKA signaling enhances SREBP1c interaction with PIAS4, promoting SREBP1c SUMOylation and subsequent ubiquitin-mediated degradation, suppressing the hepatic lipogenic program—the first demonstration of a phosphorylation-SUMOylation switch on a PIAS4 substrate.

    Evidence In vivo SUMOylation, mutagenesis, co-IP, primary hepatocytes, db/db mouse model, shRNA

    PMID:24379443

    Open questions at the time
    • Whether PIAS4 itself is regulated by PKA unknown
    • Other metabolic substrates of PIAS4 not explored
  11. 2016 High

    The FIEL1–PKCζ–GSK3β axis was identified as a second ubiquitin-dependent pathway controlling PIAS4 stability, complementing TRIM32; FIEL1-mediated PIAS4 degradation requires sequential phosphorylation of PIAS4 by PKCζ and FIEL1 by GSK3β, and drives TGF-β signaling in pulmonary fibrosis.

    Evidence Co-IP, ubiquitination assay, kinase assay, siRNA, bleomycin mouse model

    PMID:27162139

    Open questions at the time
    • Relative contributions of TRIM32 versus FIEL1 in different tissues unknown
    • Phosphorylation sites on PIAS4 not mapped
  12. 2017 High

    NMR-based structural analysis identified a second SIM in the PIAS4 C-terminus; both SIMs are required for full SUMO E3 ligase activity, providing the first structural insight into PIAS4's catalytic mechanism.

    Evidence NMR chemical shift mapping, mutagenesis, in vitro SUMOylation assay

    PMID:28455449

    Open questions at the time
    • Full-length structure of PIAS4 not solved
    • How dual SIMs cooperate mechanistically during substrate SUMOylation not resolved
  13. 2018 High

    PIAS4 (with PIAS1) was shown to SUMOylate PCNA at Lys164, promoting error-free template-switch DNA damage tolerance; double-knockout cells lose >90% of template switching, rescued by a PCNA-SUMO chimera, placing PIAS4 in the replication stress response.

    Evidence DT40 and TK6 double-knockout cells, Ig gene conversion assay, epistasis analysis, PCNA-SUMO chimera complementation

    PMID:30487218

    Open questions at the time
    • Whether PIAS4 acts at the replication fork or post-replicatively unclear
    • Relative contributions of PIAS1 versus PIAS4 to PCNA SUMOylation not fully resolved
  14. 2021 High

    PIAS4 was placed in the homologous recombination pathway: it facilitates BRCA1 recruitment and DSB end resection in an epistatic pathway with RNF4, counteracting 53BP1/RIF1-mediated resection blockade, mechanistically connecting its DSB-proximal SUMOylation to pathway choice between HR and NHEJ.

    Evidence siRNA knockdown combinations, γ-irradiation, RAD51/BRCA1/RIF1 foci quantification, epistasis analysis

    PMID:35007836

    Open questions at the time
    • Direct substrate whose SUMOylation promotes resection not identified
    • Whether PIAS4 influences NHEJ independently of HR pathway not tested
  15. 2024 High

    PIAS4 was shown to SUMOylate WRN helicase when inhibitor-trapped on chromatin, feeding into the PIAS4-RNF4 axis for p97/VCP-dependent extraction and proteasomal degradation, revealing a SUMO-targeted ubiquitin-dependent chromatin extraction mechanism with therapeutic implications in MSI-H cancers.

    Evidence Single-molecule tracking, phenotypic screen, siRNA knockdown, proteasome inhibitor treatment, xenograft model

    PMID:39025847

    Open questions at the time
    • Whether PIAS4 extracts other trapped helicases or DNA-bound proteins via the same mechanism unknown
    • Structural basis for PIAS4 recognition of chromatin-trapped substrates undefined
  16. 2026 High

    PIAS4-mediated SUMOylation of CDK6 was found to enhance Cyclin D1 binding and RB1 phosphorylation, promoting G1/S cell cycle progression, extending PIAS4's functional repertoire to direct cell cycle kinase regulation.

    Evidence In vivo SUMOylation assay, SUMO-site mutagenesis, CDK6 kinase activity assay, flow cytometry, xenograft model

    PMID:41946996

    Open questions at the time
    • Whether PIAS4 SUMOylates CDK4 or other CDKs not tested
    • How PIAS4 is regulated during cell cycle progression unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • Despite extensive substrate cataloguing, a full-length structure of PIAS4 is lacking, the mechanism by which it achieves substrate selectivity among dozens of targets is not understood, and the relative physiological importance of its E3-ligase-dependent versus E3-ligase-independent (HDAC/SAP-mediated) functions in vivo remains poorly defined.
  • No full-length structure of PIAS4
  • Substrate selectivity mechanism undefined
  • Quantitative contribution of SUMO-independent versus SUMO-dependent functions in tissues not resolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016874 ligase activity 15 GO:0140110 transcription regulator activity 6 GO:0098772 molecular function regulator activity 3
Localization
GO:0005634 nucleus 6 GO:0005694 chromosome 4 GO:0000228 nuclear chromosome 2
Pathway
R-HSA-74160 Gene expression (Transcription) 8 R-HSA-162582 Signal Transduction 7 R-HSA-392499 Metabolism of proteins 7 R-HSA-73894 DNA Repair 5 R-HSA-1640170 Cell Cycle 4 R-HSA-168256 Immune System 3 R-HSA-5357801 Programmed Cell Death 1
Partners
FIP200HDAC1KIAA0317RBX2RNF4TRIM32UBC9

Evidence

Reading pass · 43 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 PIASy (PIAS4) functions as a SUMO E3 ligase for LEF1, stimulating its sumoylation both in vivo and in a reconstituted in vitro system, and represses LEF1 transcriptional activity by sequestering it into nuclear bodies via binding to nuclear matrix-associated DNA sequences. Reconstituted in vitro SUMOylation assay, co-immunoprecipitation, nuclear fractionation, reporter gene assays Genes & development High 11731474
2003 PIASy enhances both SUMO-1 and SUMO-3 modification of C/EBPalpha at its synergy control (SC) motif (Lys159) in vivo and in vitro, thereby limiting transcriptional synergy at compound response elements. In vitro SUMOylation assay with purified recombinant components, in vivo sumoylation assay, reporter gene assays, site-directed mutagenesis The Journal of biological chemistry High 12511558
2003 PIASy interacts with Smad3 (and Smad4) through the C-terminal domain of Smad3, represses TGF-beta/Smad transcriptional activity, and promotes sumoylation of Smad3 in vivo; PIASy also interacts constitutively with HDAC1, and HDAC inhibitor trichostatin A abolishes PIASy's inhibitory function. Yeast three-hybrid screen, co-immunoprecipitation, reporter gene assays, in vivo sumoylation assay, HDAC inhibitor treatment Proceedings of the National Academy of Sciences of the United States of America High 12815042 12904571
2003 PIASy enhances conjugation of SUMO-2 to GATA-2 via its E3 SUMO ligase activity and suppresses GATA-2-dependent endothelin-1 promoter activity; this repression requires PIASy interaction with GATA-2 through both N-terminal and C-terminal sequences but is independent of the RING-like domain. In vivo sumoylation assay, co-immunoprecipitation, reporter gene assays, deletion mutagenesis Circulation research High 12750312
2003 PIASy stimulates SUMO-1 conjugation to c-Myb at K503 and K527, shifts c-Myb to the nuclear insoluble matrix fraction, and negatively regulates c-Myb transcriptional activity. In vitro SUMOylation assay, co-immunoprecipitation, reporter gene assays, mutagenesis, nuclear fractionation European journal of biochemistry High 12631292
2004 PIASy represses androgen receptor (AR) transcriptional activity by binding its RING-finger-like domain and recruiting HDAC1/HDAC2 through its RD1 repression domain; this repression is independent of PIASy's SUMO E3 ligase activity and AR sumoylation status. Co-immunoprecipitation, reporter gene assays, SUMO-ligase-deficient mutant analysis, HDAC inhibitor treatment, mutagenesis of AR sumoylation sites Oncogene High 14981544
2004 In Xenopus, PIASy is specifically required for mitotic SUMO-2 conjugation of Topoisomerase-II on chromosomes; PIASy binds mitotic chromosomes, recruits Ubc9 to chromatin, and its depletion eliminates chromosomal SUMO-2-conjugated species and blocks anaphase sister chromatid segregation. Xenopus egg extract depletion/reconstitution, immunofluorescence, chromatin-binding assay, functional chromosome segregation assay The EMBO journal High 15933717
2005 SUMO-1 modification of PIASy itself at Lys35 is required for PIASy-dependent sumoylation and transcriptional activation of Tcf-4; the K35R mutant loses the ability to enhance Tcf-4 sumoylation and transcriptional activity and shows altered nuclear distribution with increased association with PML bodies. Mutagenesis, in vivo sumoylation assay, reporter gene assays, immunofluorescence Molecular and cellular biology High 15831457
2006 PIASy is the SUMO E3 ligase for NEMO (IKKγ), preferentially mediating site-selective SUMO-1 modification; PIASy-NEMO interaction increases upon genotoxic stress and occurs in the nucleus mutually exclusive with IKK interaction, and PIASy knockdown inhibits NEMO sumoylation and NF-κB activation in response to genotoxic agents. siRNA knockdown, in vitro SUMOylation assay, co-immunoprecipitation, nuclear fractionation, reporter gene assays Nature cell biology High 16906147
2006 Overexpression of PIASy in normal human fibroblasts induces cellular senescence by stimulating sumoylation and transcriptional activity of p53 and increasing Rb-dependent corepression at E2F-responsive promoters; in Rb-deficient fibroblasts, PIASy expression causes p53-dependent apoptosis; fibroblasts lacking PIASy have reduced propensity to undergo senescence. Overexpression, knockout fibroblasts, reporter gene assays, chromatin immunoprecipitation, SUMO ligase-dead mutant analysis Molecular cell High 16793547
2006 TRIM32, an E3 ubiquitin ligase, interacts with PIASy and promotes PIASy ubiquitination and proteasomal degradation; this interaction is induced by UVB/TNFα treatment and involves redistribution of PIASy from nucleus to cytoplasm; TRIM32-mediated PIASy destabilization requires an intact RING domain in TRIM32. Co-immunoprecipitation, in vitro ubiquitination assay with purified components, immunofluorescence, RING domain mutagenesis The Journal of biological chemistry High 16816390
2006 PIASy is a novel interaction partner and SUMO-E3 ligase for Ets-1; PIASy represses Ets-1-dependent transcription independently of Ets-1 sumoylation status (repression depends on sumoylation of other factors); PIASy also prevents proteasomal degradation of Ets-1 by stabilizing it. Co-immunoprecipitation, in vivo sumoylation assay, reporter gene assays, RNAi knockdown, proteasome inhibitor treatment Biochemical and biophysical research communications / The Biochemical journal High 16729975 17456046
2007 PIASy stimulates sumoylation of YY1 at Lys288 in vivo and in vitro; uniquely, PIASy-mediated YY1 sumoylation depends on YY1-PIASy protein interaction but not on the RING finger domain of PIASy (unlike all other known PIASy substrates); PIASy colocalizes with YY1 in the nucleus and stabilizes YY1 protein. In vitro SUMOylation assay, co-immunoprecipitation, mutagenesis, reporter gene assays, immunofluorescence Molecular and cellular biology High 17353273
2007 PIASy deletion in dendritic cells results in enhanced expression of a subset of NF-κB and STAT1-dependent genes in response to LPS or IFN-γ; Pias1/Piasy double-knockout embryos die before E11.5, demonstrating functional cooperation between PIAS1 and PIASy in controlling NF-κB/STAT1-mediated gene activation. Gene knockout mice, gene expression analysis, LPS challenge, IFN-γ treatment, double-knockout embryo analysis Proceedings of the National Academy of Sciences of the United States of America High 17606919
2008 PIASy-mediated sumoylation of Smad3 stimulates its nuclear export; co-expression of Smad3 with PIASy and SUMO1 reduces Smad3 DNA-binding activity and promotes cytoplasmic translocation; FRET analyses confirmed Smad3-SUMO1 interaction in the cytoplasm. siRNA knockdown, co-immunoprecipitation, FRET analysis, nuclear export assay, reporter gene assays Biochemical and biophysical research communications High 18384750
2008 PIASy represses C/EBPdelta transcriptional activity by sequestering it to the nuclear periphery via interaction between the PIASy SAPD (N-terminal nuclear matrix binding domain) and the C/EBPdelta transactivation domain; this repression is independent of HDAC activity and PIASy E3 SUMO ligase activity. Reporter gene assays, deletion mutagenesis, immunofluorescence, co-immunoprecipitation The Journal of biological chemistry High 18477566
2008 PIASy interacts with FIP200 via its RING finger domain; PIASy redistributes FIP200 from the cytoplasm to the nucleus, abrogating FIP200 regulation of TSC/S6K signaling; FIP200 and PIASy are co-recruited to the p21 promoter, and FIP200 is required for PIASy transcriptional activation of p21. Co-immunoprecipitation, immunofluorescence, subcellular fractionation, chromatin immunoprecipitation, RNAi Molecular and cellular biology High 18285457
2009 PIAS4 accumulates at DNA double-strand break sites via mechanisms requiring its SAP domain; PIAS4 promotes SUMO1 and SUMO2/3 accrual at DSB sites, and is required for productive association of 53BP1, BRCA1, and RNF168 with damage sites; PIAS4 is required for effective ubiquitin-adduct formation by RNF8, RNF168, and BRCA1, and promotes DSB repair. Immunofluorescence, siRNA knockdown, laser micro-irradiation, IRIF quantification, clonogenic survival assay Nature High 20016603
2010 PIASy interacts with VHL and induces VHL SUMOylation at Lys171 by SUMO1; PIASy-mediated SUMOylation of VHL induces VHL oligomerization and abrogates its inhibitory function on tumor cell growth, migration, and clonogenicity; PIASy knockdown reduces VHL oligomerization and increases HIF1α degradation. Co-immunoprecipitation, in vivo SUMOylation assay, siRNA knockdown, site-directed mutagenesis, functional tumor assays PloS one High 20300531
2010 PIASy stimulates SUMO-2/3 modification of TopoIIα at Lys660 in the DNA gate domain; this SUMOylation strongly inhibits TopoIIα decatenation activity; loss of SUMOylation on Lys660 eliminates PIASy-mediated inhibition of TopoIIα activity. Mass spectrometry, in vitro SUMOylation assay, decatenation activity assay, site-directed mutagenesis The Journal of cell biology High 21079245
2010 PIASy promotes SUMO-2/3 conjugation of PARP1 at Lys482 on mitotic chromosomes; PARP1 SUMOylation does not alter its intrinsic enzyme activity but controls PARP1's capacity to poly-ADP-ribosylate other chromatin-associated proteins. Xenopus egg extract reconstitution, tandem mass spectrometry, in vitro SUMOylation assay, mutagenesis, PAR activity assay The Journal of biological chemistry High 20228053
2010 PIASy stimulates HIF1α SUMOylation by SUMO1 in a hypoxia-dependent manner; hypoxia promotes HIF1α nuclear translocation to enable PIASy binding; PIASy negatively regulates hypoxia-induced HIF1α stability and transactivation, and PIASy knockdown increases angiogenic activity. Co-immunoprecipitation, in vivo SUMOylation assay, siRNA knockdown, reporter gene assays, angiogenesis assay Oncogene High 20661221
2010 The N-terminal domain of PIASy is sufficient for centromeric localization and interacts with the Rod/Zw10 kinetochore complex; swapping PIASy's N terminus with other PIAS family members abolishes chromosomal binding and mitotic SUMOylation; depletion of Rod compromises centromeric localization of PIASy and SUMO2/3. Xenopus egg extract depletion, immunofluorescence, co-immunoprecipitation, truncation mutagenesis The Journal of biological chemistry High 20696768
2011 PIASy inhibits virus-induced type I IFN transcription via a mechanism requiring its SUMO-interacting motif (SIM) and the SUMO modification machinery (UBC9), but independent of its SUMO E3 ligase activity; PIASy inhibits IFN-stimulated gene expression via a distinct LXXLL motif in its SAP domain. PIASy knockout cells, overexpression, reporter gene assays, site-directed mutagenesis of LXXLL and SIM motifs, UBC9 knockdown The Journal of biological chemistry High 21199872
2011 PIAS4 (PIASy) interacts with the tumor suppressor VHL, induces VHL sumoylation, and overexpression of PIAS4 stimulates expression of HIF1α target genes (VEGF, STAT3) by impairing VHL function; PIAS4 siRNA suppresses HIF1α and these target genes in pancreatic cancer cells. Co-immunoprecipitation, siRNA knockdown, Western blotting, gene expression analysis British journal of cancer Medium 24002598
2011 SYT-SSX1 oncoprotein interacts with PIASy and increases PIASy-mediated sumoylation of NCOA3 and NEMO, leading to increased NCOA3 steady-state levels and nuclear localization. Co-immunoprecipitation, in vivo sumoylation assay, Western blotting The Journal of biological chemistry Medium 21454665
2011 PIASy acts as a SUMO E3 ligase for caveolin-3 (Cav-3); Cav-3 is SUMOylated at a consensus motif near the scaffolding domain; SUMOylation-deficient Cav-3 alters β2-adrenergic receptor expression after agonist stimulation but not β1AR, implicating Cav-3 SUMOylation in β2AR desensitization. Co-immunoprecipitation, site-directed mutagenesis, in vivo SUMOylation assay, receptor expression assays The Journal of biological chemistry High 21362625
2013 PIASy (PIAS4) is induced by hypoxia and mediates SUMOylation of Sp1, preventing Sp1 from binding to the SIRT1 promoter and thereby transcriptionally repressing SIRT1 in ovarian cancer cells; PIASy knockdown restores Sp1 binding and SIRT1 expression, reverses EMT, and attenuates metastasis in vivo. siRNA knockdown, chromatin immunoprecipitation, reporter gene assays, in vivo xenograft model Journal of cell science High 23843607
2013 PIASy sumoylates SREBP1c at Lys98, leading to suppression of the hepatic lipogenic program upon fasting-induced PKA signaling; PKA phosphorylation of SREBP1c enhances its interaction with PIASy and promotes sumoylation, which subsequently triggers ubiquitin-mediated degradation of SREBP1c. In vivo sumoylation assay, mutagenesis, co-immunoprecipitation, primary hepatocytes, db/db mouse model, shRNA knockdown Molecular and cellular biology High 24379443
2015 PIAS4 specifically SUMOylates AMPKα1; PIAS4 E3 ligase activity attenuates AMPKα1 activity specifically towards mTORC1 signaling and is required for rapid AMPK inactivation to allow mTORC1 restoration; SUMOylation-deficient AMPKα1 shows higher activity toward mTORC1 when reconstituted in AMPKα-deficient cells. In vivo SUMOylation assay, PIAS4 siRNA/knockout, AMPKα-deficient reconstitution, mTORC1 signaling assays, mutagenesis Nature communications High 26616021
2016 FIEL1 (KIAA0317), an E3 ubiquitin ligase, targets PIAS4 for site-specific ubiquitination and degradation; PIAS4 degradation requires phosphorylation of PIAS4 by PKCζ and phosphorylation of FIEL1 by GSK3β; FIEL1 overexpression promotes TGF-β signaling through PIAS4 reduction, contributing to lung fibrosis. Co-immunoprecipitation, ubiquitination assay, kinase assay, siRNA knockdown, overexpression, bleomycin mouse model The Journal of experimental medicine High 27162139
2016 PIAS4 promotes restriction of HSV-1 through intrinsic antiviral immunity; PIAS4 is upregulated during HSV-1 infection and localizes to nuclear domains containing viral DNA via SIM-dependent mechanisms (for early entry sites) and SIM-independent mechanisms (for replication compartments); PIAS4 depletion enhances replication of ICP0-null HSV-1. siRNA knockdown, immunofluorescence, viral replication assay, confocal microscopy Journal of virology High 26937035
2016 HDAC9-mediated de-acetylation of Nkx3.2 triggers PIASy-mediated sumoylation, which is followed by RNF4-mediated SUMO-targeted ubiquitination, controlling Nkx3.2 protein stability and chondrocyte hypertrophic maturation. Co-immunoprecipitation, in vivo sumoylation/ubiquitination assays, reporter gene assays, mutagenesis Cellular signalling High 27312341
2017 PIAS4 is the primary SUMO E3 ligase for RIF1 SUMOylation in response to DNA damage; PIAS4 knockdown impairs RIF1 SUMOylation, abrogates UHRF1-dependent ubiquitination of RIF1, and compromises disassembly of RIF1 DNA damage response foci, leading to genomic instability. siRNA knockdown, immunofluorescence, co-immunoprecipitation, ubiquitination assay Scientific reports Medium 29234018
2017 PIAS4 is a SUMO E3 ligase for ORC2 at the G2/M phase; PIAS4 depletion or SENP2 overexpression eliminates ORC2 SUMOylation, resulting in abnormal centromeric histone H3K4 methylation and polyploidy. siRNA knockdown, in vivo SUMOylation assay, flow cytometry, histone modification analysis Oncotarget Medium 29050267
2017 PIASy contains two SUMO-interacting motifs (SIMs) at its C-terminus; NMR chemical shift mapping identified a new SIM in addition to the previously known SIM; both SIMs are required for the full SUMO E3 ligase activity of PIASy. NMR chemical shift mapping, mutagenesis, in vitro SUMOylation assay The Journal of biological chemistry High 28455449
2018 PIAS1 and PIAS4 promote template switch (error-free) DNA damage tolerance by SUMOylating PCNA at Lys164; PIAS1/PIAS4 double-knockout cells show >90% decrease in PCNA-Lys164 SUMOylation and template switch, and overexpression of a PCNA-SUMO1 chimera restores this defect. Genetic knockout (DT40 and TK6 cells), Ig gene conversion assay, epistasis analysis, PCNA-SUMO chimera complementation Proceedings of the National Academy of Sciences of the United States of America High 30487218
2019 PIAS4 SUMOylates DPPA2, negatively regulating its transcriptional activity and preventing activation of the 2C-like transcriptional program (DUX) during zygotic genome activation; depletion of PIAS4 or overexpression of DPPA2/4 is sufficient to activate 2C-like transcriptional program. siRNA knockdown, overexpression, in vivo sumoylation assay, reporter gene assays, mouse embryo development assay PLoS biology High 31226106
2021 PIAS4 promotes DSB repair by homologous recombination by facilitating BRCA1 recruitment, enabling DSB end resection and RAD51 loading, in an epistatic pathway with RNF4 and BRCA1 that counteracts 53BP1/RIF1-mediated resection blockade. siRNA knockdown, γ-ray irradiation, immunofluorescence for RAD51/BRCA1/RIF1 foci, epistasis analysis Biochemical and biophysical research communications High 35007836
2024 PIAS4 mediates SUMOylation of SLC7A11 via direct binding; KDM1A acts as a transcriptional activator of PIAS4; inhibition of PIAS4-dependent SUMOylation of SLC7A11 by tanshinone IIA (via KDM1A suppression) destabilizes SLC7A11 and induces ferroptosis in breast cancer. Co-immunoprecipitation, Ni-beads pulldown for SUMOylation, ChIP assay, luciferase assay, siRNA knockdown, xenograft model Journal of advanced research High 38615741
2024 PIAS4 mediates SUMOylation of WRN helicase when it is inhibitor-trapped on chromatin; the PIAS4-RNF4 axis is responsible for WRN extraction and proteasomal degradation via p97/VCP; co-inhibition of WRN and SUMOylation has additive toxicity in MSI-H cancer cells. Single-molecule tracking, phenotypic screen, siRNA knockdown, proteasome inhibitor treatment, xenograft model Nature communications High 39025847
2025 PIAS1 and PIAS4 facilitate SUMOylation of TDP-43 by SUMO1 and SUMO2/3 in response to oxidative stress; specific regions of TDP-43 were identified as SUMOylation sites. In vivo SUMOylation assay, oxidative stress treatment, siRNA knockdown bioRxivpreprint Low 41292941
2026 PIAS4 mediates SUMO1 and SUMO2/3 modification of CDK6; CDK6 SUMOylation enhances RB1 phosphorylation and downstream cell cycle gene transcription; mutation of SUMO2/3 modification sites on CDK6 inhibits CDK6-mediated RB1 phosphorylation and blocks G1 phase progression; PIAS4 knockdown reduces Cyclin D1 binding to CDK6. In vivo SUMOylation assay, site-directed mutagenesis, co-immunoprecipitation, flow cytometry, CDK6 kinase activity assay, xenograft model Oncogene High 41946996

Source papers

Stage 0 corpus · 85 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 PIASy, a nuclear matrix-associated SUMO E3 ligase, represses LEF1 activity by sequestration into nuclear bodies. Genes & development 456 11731474
2009 Mammalian SUMO E3-ligases PIAS1 and PIAS4 promote responses to DNA double-strand breaks. Nature 439 20016603
2006 PIASy mediates NEMO sumoylation and NF-kappaB activation in response to genotoxic stress. Nature cell biology 184 16906147
2006 The E3 SUMO ligase PIASy is a regulator of cellular senescence and apoptosis. Molecular cell 144 16793547
2003 A synergy control motif within the attenuator domain of CCAAT/enhancer-binding protein alpha inhibits transcriptional synergy through its PIASy-enhanced modification by SUMO-1 or SUMO-3. The Journal of biological chemistry 126 12511558
2005 PIASy mediates SUMO-2 conjugation of Topoisomerase-II on mitotic chromosomes. The EMBO journal 123 15933717
2003 Repression of Smad transcriptional activity by PIASy, an inhibitor of activated STAT. Proceedings of the National Academy of Sciences of the United States of America 94 12904571
2019 DPPA2/4 and SUMO E3 ligase PIAS4 opposingly regulate zygotic transcriptional program. PLoS biology 82 31226106
2013 PIASy mediates hypoxia-induced SIRT1 transcriptional repression and epithelial-to-mesenchymal transition in ovarian cancer cells. Journal of cell science 77 23843607
2004 Protein inhibitor of activated STAT Y (PIASy) and a splice variant lacking exon 6 enhance sumoylation but are not essential for embryogenesis and adult life. Molecular and cellular biology 76 15169916
2007 PIASy-mediated sumoylation of Yin Yang 1 depends on their interaction but not the RING finger. Molecular and cellular biology 75 17353273
2006 The interaction of Piasy with Trim32, an E3-ubiquitin ligase mutated in limb-girdle muscular dystrophy type 2H, promotes Piasy degradation and regulates UVB-induced keratinocyte apoptosis through NFkappaB. The Journal of biological chemistry 75 16816390
2003 Regulation of transforming growth factor-beta signaling by protein inhibitor of activated STAT, PIASy through Smad3. The Journal of biological chemistry 75 12815042
2010 Hypoxia inactivates the VHL tumor suppressor through PIASy-mediated SUMO modification. PloS one 73 20300531
2007 Control of specificity and magnitude of NF-kappa B and STAT1-mediated gene activation through PIASy and PIAS1 cooperation. Proceedings of the National Academy of Sciences of the United States of America 72 17606919
2004 PIASy-mediated repression of the androgen receptor is independent of sumoylation. Oncogene 71 14981544
2004 PIASy-deficient mice display modest defects in IFN and Wnt signaling. Journal of immunology (Baltimore, Md. : 1950) 69 15528356
2010 PIASy stimulates HIF1α SUMOylation and negatively regulates HIF1α activity in response to hypoxia. Oncogene 63 20661221
2010 PIASy-dependent SUMOylation regulates DNA topoisomerase IIalpha activity. The Journal of cell biology 63 21079245
2003 Transactivation properties of c-Myb are critically dependent on two SUMO-1 acceptor sites that are conjugated in a PIASy enhanced manner. European journal of biochemistry 61 12631292
2001 A putative protein inhibitor of activated STAT (PIASy) interacts with p53 and inhibits p53-mediated transactivation but not apoptosis. Apoptosis : an international journal on programmed cell death 57 11388671
2003 Modification of GATA-2 transcriptional activity in endothelial cells by the SUMO E3 ligase PIASy. Circulation research 55 12750312
2010 Regulation of the psoriatic chemokine CCL20 by E3 ligases Trim32 and Piasy in keratinocytes. The Journal of investigative dermatology 54 20054338
2010 PIASy mediates SUMO-2/3 conjugation of poly(ADP-ribose) polymerase 1 (PARP1) on mitotic chromosomes. The Journal of biological chemistry 51 20228053
2005 SUMO-1 modification of PIASy, an E3 ligase, is necessary for PIASy-dependent activation of Tcf-4. Molecular and cellular biology 50 15831457
2008 Sumoylation of Smad3 stimulates its nuclear export during PIASy-mediated suppression of TGF-beta signaling. Biochemical and biophysical research communications 49 18384750
2013 PIASy-mediated sumoylation of SREBP1c regulates hepatic lipid metabolism upon fasting signaling. Molecular and cellular biology 48 24379443
2011 mRNA expression of BRCA1, PIAS1, and PIAS4 and survival after second-line docetaxel in advanced gastric cancer. Journal of the National Cancer Institute 47 21862729
2005 Interactions between coilin and PIASy partially link Cajal bodies to PML bodies. Journal of cell science 47 16219678
2006 Interaction of moloney murine leukemia virus capsid with Ubc9 and PIASy mediates SUMO-1 addition required early in infection. Journal of virology 42 16352559
2013 PIAS4 is an activator of hypoxia signalling via VHL suppression during growth of pancreatic cancer cells. British journal of cancer 40 24002598
2015 SUMOylation of AMPKα1 by PIAS4 specifically regulates mTORC1 signalling. Nature communications 39 26616021
2004 PIASy represses TRIF-induced ISRE and NF-kappaB activation but not apoptosis. FEBS letters 38 15251447
2012 Characterization of a PIAS4 homologue from zebrafish: insights into its conserved negative regulatory mechanism in the TRIF, MAVS, and IFN signaling pathways during vertebrate evolution. Journal of immunology (Baltimore, Md. : 1950) 36 22345667
2016 Novel Role for Protein Inhibitor of Activated STAT 4 (PIAS4) in the Restriction of Herpes Simplex Virus 1 by the Cellular Intrinsic Antiviral Immune Response. Journal of virology 35 26937035
2018 SUMOylation of PCNA by PIAS1 and PIAS4 promotes template switch in the chicken and human B cell lines. Proceedings of the National Academy of Sciences of the United States of America 34 30487218
2024 Tanshinone IIA destabilizes SLC7A11 by regulating PIAS4-mediated SUMOylation of SLC7A11 through KDM1A, and promotes ferroptosis in breast cancer. Journal of advanced research 33 38615741
2016 Ubiquitin E3 ligase FIEL1 regulates fibrotic lung injury through SUMO-E3 ligase PIAS4. The Journal of experimental medicine 33 27162139
2011 PIASy inhibits virus-induced and interferon-stimulated transcription through distinct mechanisms. The Journal of biological chemistry 32 21199872
2008 PIASy represses CCAAT/enhancer-binding protein delta (C/EBPdelta) transcriptional activity by sequestering C/EBPdelta to the nuclear periphery. The Journal of biological chemistry 30 18477566
2006 PIASy-mediated repression of the Ets-1 is independent of its sumoylation. Biochemical and biophysical research communications 29 16729975
2011 Caveolin-3 undergoes SUMOylation by the SUMO E3 ligase PIASy: sumoylation affects G-protein-coupled receptor desensitization. The Journal of biological chemistry 27 21362625
2016 Transcriptional repression of SIRT1 by protein inhibitor of activated STAT 4 (PIAS4) in hepatic stellate cells contributes to liver fibrosis. Scientific reports 24 27323886
2004 Convergence of interferon-gamma and progesterone signaling pathways in human endometrium: role of PIASy (protein inhibitor of activated signal transducer and activator of transcription-y). Molecular endocrinology (Baltimore, Md.) 23 15155784
2008 Spatial interplay between PIASy and FIP200 in the regulation of signal transduction and transcriptional activity. Molecular and cellular biology 22 18285457
2018 Alcohol-induced autophagy via upregulation of PIASy promotes HCV replication in human hepatoma cells. Cell death & disease 20 30185779
2010 Rod/Zw10 complex is required for PIASy-dependent centromeric SUMOylation. The Journal of biological chemistry 20 20696768
2007 PIASy controls ubiquitination-dependent proteasomal degradation of Ets-1. The Biochemical journal 19 17456046
2017 SUMO E3 Ligase PIASy Mediates High Glucose-Induced Activation of NF-κB Inflammatory Signaling in Rat Mesangial Cells. Mediators of inflammation 17 29038616
2017 Dynamics of RIF1 SUMOylation is regulated by PIAS4 in the maintenance of Genomic Stability. Scientific reports 17 29234018
2016 A post-translational modification cascade employing HDAC9-PIASy-RNF4 axis regulates chondrocyte hypertrophy by modulating Nkx3.2 protein stability. Cellular signalling 16 27312341
2024 WRN inhibition leads to its chromatin-associated degradation via the PIAS4-RNF4-p97/VCP axis. Nature communications 15 39025847
2019 Perturbation of maternal PIASy abundance disrupts zygotic genome activation and embryonic development via SUMOylation pathway. Biology open 14 31640975
2017 Identification of a new small ubiquitin-like modifier (SUMO)-interacting motif in the E3 ligase PIASy. The Journal of biological chemistry 14 28455449
2009 PIASy inhibits LRH-1-dependent CYP11A1 expression by competing for SRC-1 binding. The Biochemical journal 14 19067654
2017 Immunosuppression with tacrolimus improved implantation and rescued expression of uterine progesterone receptor and its co-regulators FKBP52 and PIASy at nidation in the obese and diabetic mice: Comparative studies with metformin. Molecular and cellular endocrinology 13 28689771
2010 PIASy interacts with p73alpha and regulates cell cycle in HEK293 cells. Cellular immunology 13 20471636
2022 Cardiac-targeted PIASy gene silencing mediates deSUMOylation of caveolin-3 and prevents ischemia/reperfusion-induced Nav1.5 downregulation and ventricular arrhythmias. Military Medical Research 12 36229865
2020 PIAS4, upregulated in hepatocellular carcinoma, promotes tumorigenicity and metastasis. Journal of cellular biochemistry 12 31943317
2004 The RING domain of PIASy is involved in the suppression of bone morphogenetic protein-signaling pathway. Biochemical and biophysical research communications 12 15158472
2023 Downregulation of cardiac PIASy inhibits Cx43 SUMOylation and ameliorates ventricular arrhythmias in a rat model of myocardial ischemia/reperfusion injury. Chinese medical journal 11 37014755
2012 PIAS4 represses vitamin D receptor-mediated signaling and acts as an E3-SUMO ligase towards vitamin D receptor. The Journal of steroid biochemistry and molecular biology 11 22564762
2011 SYT-SSX1 (synovial sarcoma translocated) regulates PIASy ligase activity to cause overexpression of NCOA3 protein. The Journal of biological chemistry 10 21454665
2018 Chromatin remodeling: demethylating H3K4me3 of type I IFNs gene by Rbp2 through interacting with Piasy for transcriptional attenuation. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 9 28970247
2013 Protein inhibitors of activated STAT (Pias1 and Piasy) differentially regulate pituitary homeobox 2 (PITX2) transcriptional activity. The Journal of biological chemistry 9 23515314
2004 Negative regulation of Smad2 by PIASy is required for proper Xenopus mesoderm formation. Development (Cambridge, England) 9 15496439
2020 Homeoprotein Msx1-PIASy Interaction Inhibits Angiogenesis. Cells 8 32784646
2019 PIASy is a SUMOylation-independent negative regulator of the insulin transactivator MafA. Journal of molecular endocrinology 8 31614335
2016 Protein inhibitor of activated STAT 4 (PIAS4) regulates liver fibrosis through modulating SMAD3 activity. Journal of biomedical research 8 27924068
2016 Protein inhibitor of activated STAT 4 (PIAS4) regulates pro-inflammatory transcription in hepatocytes by repressing SIRT1. Oncotarget 7 27285989
2016 Protein Inhibitor of Activated STAT Y (PIASy) Regulates Insulin Secretion by Interacting with LIM Homeodomain Transcription Factor Isl1. Scientific reports 7 28000708
2013 Impaired PIASy-Tip60 signaling weakens activation of p53 in melanoma. Melanoma research 7 23624367
2012 Protein inhibitor of activated STAT, PIASy regulates α-smooth muscle actin expression by interacting with E12 in mesangial cells. PloS one 7 22829926
2021 Roles of the SUMO-related enzymes, PIAS1, PIAS4, and RNF4, in DNA double-strand break repair by homologous recombination. Biochemical and biophysical research communications 5 35007836
2017 Reversible regulation of ORC2 SUMOylation by PIAS4 and SENP2. Oncotarget 4 29050267
2014 SUMO Proteins are not Involved in TGF-β1-induced, Smad3/4-mediated Germline α Transcription, but PIASy Suppresses it in CH12F3-2A B Cells. Immune network 4 25550698
2018 PIASy antagonizes Ras-driven NSCLC survival by promoting GATA2 SUMOylation. Journal of Cancer 3 29760808
2025 Total Flavonoids of Hedyotis Diffusa Willd Suppresses Prostate Cancer Progression by Promoting AR Ubiquitination and Degradation via the PIAS4/STAT3 Pathway. Cell biology international 2 40862474
2024 PIAS4 regulates pluripotency exit and cell fate commitment in porcine embryonic stem cells. Fundamental research 2 40777776
2025 PIASy deficiency mitigates thoracic aortic aneurysm formation via the TGF-β/Smad2/3 pathway. Journal of thoracic disease 1 40529770
2026 SUMOylation machinery protein, PIAS4 role in breast cancer cell proliferation and drug sensitivity. Molecular biology reports 0 41615552
2026 SIRT5 Inhibits HMGCS2 Succinylation and Promotes Its PIAS4-Dependent Ubiquitination to Attenuate Diabetic Cardiomyopathy. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 0 41626766
2026 PIAS4 inhibition induces cell cycle arrest and exhibits a synergistic effect in combination with CDK4/6 inhibitor in breast cancer treatment. Oncogene 0 41946996
2025 PIASy of orange-spotted grouper (Epinephelus coioides) negatively regulates RLRs-mediated innate antiviral immunity. Fish & shellfish immunology 0 39842679
2025 PIAS1/PIAS4-Mediated SUMOylation of TDP-43 Is Induced by Oxidative Stress. bioRxiv : the preprint server for biology 0 41292941