family_id: PANTHER:PTHR10782 family_name: ZINC FINGER MIZ DOMAIN-CONTAINING PROTEIN preferred_name: PIAS/Siz family of SP-RING SUMO ligases (PIAS1-4, ZMIZ1/2, Siz1/Siz2/Pli1, plant SIZ1 and PIAL1/2) summary: >- Eukaryotic SP-RING (Siz/PIAS RING, also called MIZ-type zinc finger) proteins. The SP-RING is a RING-related domain that binds the SUMO E2 Ubc9/UBE2I and, like a RING E3, activates the E2~SUMO thioester for transfer to a substrate lysine; it has no catalytic cysteine and forms no E3~SUMO intermediate. Most members also carry an N-terminal SAP DNA-binding motif and a PINIT domain. The founding members, budding yeast Siz1 and Siz2, are E3-like factors that together account for most SUMO conjugation in yeast (septins at the bud neck in G2/M, PCNA during S phase). Fission yeast Pli1, Arabidopsis and rice SIZ1/SIZ2, C. elegans GEI-17, Drosophila Su(var)2-10 and vertebrate PIAS1-4 are SUMO E3 ligases for many nuclear substrates. Arabidopsis PIAL1 and PIAL2 are SP-RING ligases specialised for SUMO chain formation ("E4" activity). Vertebrate ZMIZ1 and ZMIZ2 and their invertebrate orthologs (Drosophila tonalli, C. elegans miz-1) form a separate bilaterian clade of transcriptional coregulators. They keep an intact SP-RING zinc site, but direct SUMO ligase activity has not been firmly shown. In vertebrates and flies the PIAS proteins also bind activated STAT dimers and block STAT DNA binding, a coregulator activity that often does not need the SP-RING. Plants, fungi and protists have no STAT-PIAS relationship of this kind. functional_coherence: MOSTLY_COHERENT coherence_reason: >- SUMO ligase activity and protein sumoylation are shared across the family. Ligase activity is shown directly for fungal (Siz1/Siz2, Pli1), plant (SIZ1, PIAL1/2), nematode (GEI-17), insect (Su(var)2-10) and vertebrate (PIAS1-4) members. The four SP-RING zinc ligands of PIAS1 (C351, H353, C374, C377) are conserved in every reviewed member checked, ZMIZ1/2 and PIAL1/2 included, so no lineage looks like a pseudoligase. The exceptions are not losses of ligase activity. Two groups differ in emphasis or mode: (1) the ZMIZ clade (SF7 ZMIZ1, SF38 ZMIZ2, and tonalli/miz-1 within SF4), which act mainly as transcriptional coactivators and whose ligase activity is only weakly supported; (2) plant PIAL1 (SF68) and PIAL2 (in SF4), which extend SUMO chains, still within SUMO ligase activity. STAT inhibition and JAK-STAT regulation belong to the metazoan PIAS clade (SF9, SF10, SF11, SF12, SF101, SF94). Even there, C. elegans GEI-17 inherits the JAK-STAT term although nematodes have no JAK. reference_protein: id: UniProtKB:O75925 label: E3 SUMO-protein ligase PIAS1 gene_symbol: PIAS1 organism: Homo sapiens gene_review: genes/human/PIAS1/PIAS1-ai-review.yaml subfamilies: - subfamily_id: PANTHER:PTHR10782:SF11 clade_node_id: PANTHER:PTN002583825 label: E3 SUMO-PROTEIN LIGASE PIAS1 description: >- Euteleostome PIAS1 and PIAS3. The tetrapod duplication PTN004192120 gives rise to both, so PIAS3 falls in SF11 at the node level even though PANTHER also issues a PIAS3-specific SF10 label. This is the canonical SUMO E3 group: PIAS1 sumoylates p53 and many transcription factors, and blocks Stat1 DNA binding. representative_members: - id: UniProtKB:O75925 label: PIAS1 gene_symbol: PIAS1 organism: Homo sapiens gene_review: genes/human/PIAS1/PIAS1-ai-review.yaml - id: UniProtKB:O88907 label: Pias1 gene_symbol: Pias1 organism: Mus musculus gene_review: genes/mouse/Pias1/Pias1-ai-review.yaml diverged_from_family: false - subfamily_id: PANTHER:PTHR10782:SF10 label: E3 SUMO-PROTEIN LIGASE PIAS3 description: >- Mammalian PIAS3. It is a SUMO E3 and also specifically inhibits Stat3: it blocks Stat3 DNA binding without affecting Stat1. representative_members: - id: UniProtKB:Q9Y6X2 label: PIAS3 gene_symbol: PIAS3 organism: Homo sapiens - id: UniProtKB:O54714 label: Pias3 gene_symbol: Pias3 organism: Mus musculus diverged_from_family: false - subfamily_id: PANTHER:PTHR10782:SF12 clade_node_id: PANTHER:PTN002583811 label: E3 SUMO-PROTEIN LIGASE PIAS2 description: Euteleostome PIAS2 (PIASx), SUMO E3 ligase and nuclear-receptor coregulator. representative_members: - id: UniProtKB:O75928 label: PIAS2 gene_symbol: PIAS2 organism: Homo sapiens - id: UniProtKB:Q8C5D8 label: Pias2 gene_symbol: Pias2 organism: Mus musculus diverged_from_family: false - subfamily_id: PANTHER:PTHR10782:SF9 clade_node_id: PANTHER:PTN002583817 label: E3 SUMO-PROTEIN LIGASE PIAS4 description: Euteleostome PIAS4 (PIASy), including the zebrafish pias4a/pias4l duplicates. representative_members: - id: UniProtKB:Q8N2W9 label: PIAS4 gene_symbol: PIAS4 organism: Homo sapiens - id: UniProtKB:Q9JM05 label: Pias4 gene_symbol: Pias4 organism: Mus musculus - id: UniProtKB:F1R4C4 label: pias4a gene_symbol: pias4a organism: Danio rerio diverged_from_family: false - subfamily_id: PANTHER:PTHR10782:SF101 label: E3 SUMO-PROTEIN LIGASE PIAS1 description: >- Zebrafish pias1a, a teleost PIAS1 duplicate (duplication node PTN002583829) that PANTHER labels separately from SF11. Listed only so that SF11 is not read as the whole PIAS1 group. representative_members: - id: UniProtKB:A0A1D5NSS2 label: pias1a gene_symbol: pias1a organism: Danio rerio diverged_from_family: false - subfamily_id: PANTHER:PTHR10782:SF94 clade_node_id: PANTHER:PTN000845825 label: SUPPRESSOR OF VARIEGATION 2-10, ISOFORM I description: >- The Eumetazoa node of the PIAS clade, PTN000845825. Members outside the vertebrate PIAS subfamilies fall here, chiefly Drosophila Su(var)2-10 (dPIAS) and C. elegans GEI-17. Su(var)2-10 opposes activated STAT92E. GEI-17 is a SUMO E3 that makes SUMO chains in vitro and drives mitotic SUMO conjugation. representative_members: - id: UniProtKB:Q7KNF5 label: Su(var)2-10 gene_symbol: Su(var)2-10 organism: Drosophila melanogaster gene_review: genes/DROME/Su-var-2-10/Su-var-2-10-ai-review.yaml - id: UniProtKB:Q94361 label: gei-17 gene_symbol: gei-17 organism: Caenorhabditis elegans gene_review: genes/worm/gei-17/gei-17-ai-review.yaml diverged_from_family: false - subfamily_id: PANTHER:PTHR10782:SF7 clade_node_id: PANTHER:PTN002583778 label: ZINC FINGER MIZ DOMAIN-CONTAINING PROTEIN 1 description: >- Vertebrate ZMIZ1 (Zimp10). It coactivates the androgen receptor, p53, SMAD3/4, Wnt/beta-catenin and NOTCH1 and associates with the BAF chromatin-remodeling complex. It has a strong C-terminal transactivation domain that other PIAS proteins lack. representative_members: - id: UniProtKB:Q9ULJ6 label: ZMIZ1 gene_symbol: ZMIZ1 organism: Homo sapiens - id: UniProtKB:Q6P1E1 label: Zmiz1 gene_symbol: Zmiz1 organism: Mus musculus diverged_from_family: true divergence_description: >- The main established activity is transcriptional coactivation, which PAINT places on the bilaterian ZMIZ node PTN000081664 (GO:0003713). The SP-RING zinc ligands are intact (C758, H760, C781, C784 align with PIAS1 C351/H353/C374/C377), and hZimp10 increases AR sumoylation modestly in cells. The original authors could not tell whether this is direct E3 activity. SUMO ligase activity, inherited from the family root, should be treated as plausible but not core for this group. PIAS-type STAT-inhibitor terms do not descend here and should not be added. - subfamily_id: PANTHER:PTHR10782:SF38 clade_node_id: PANTHER:PTN002583788 label: ZINC FINGER MIZ DOMAIN-CONTAINING PROTEIN 2 description: Vertebrate ZMIZ2 (Zimp7), the paralog of ZMIZ1 and likewise a transcriptional coactivator. representative_members: - id: UniProtKB:Q8NF64 label: ZMIZ2 gene_symbol: ZMIZ2 organism: Homo sapiens - id: UniProtKB:Q8CIE2 label: Zmiz2 gene_symbol: Zmiz2 organism: Mus musculus diverged_from_family: true divergence_description: >- Same as SF7. Coactivator function is primary. SP-RING zinc ligands are intact (C616, H618, C639, C642), but ligase activity is inferred rather than demonstrated. Do not treat SUMO ligase activity as a core function without direct evidence. - subfamily_id: PANTHER:PTHR10782:SF4 clade_node_id: PANTHER:PTN000081660 label: TONALLI, ISOFORM E description: >- PANTHER's default subfamily, assigned at the family root (PTN000081660, Eukaryota). It therefore collects every member not placed in a more specific subfamily, and it is phylogenetically heterogeneous. It includes the fungal Siz-type ligases (S. cerevisiae Siz1 and Siz2/Nfi1, S. pombe Pli1), Arabidopsis PIAL2, Dictyostelium members, and the invertebrate ZMIZ-clade orthologs (Drosophila tonalli, C. elegans miz-1). It is not a functional group, so no term should be scoped to SF4 as a unit. representative_members: - id: UniProtKB:Q04195 label: SIZ1 gene_symbol: SIZ1 organism: Saccharomyces cerevisiae gene_review: genes/yeast/SIZ1/SIZ1-ai-review.yaml - id: UniProtKB:Q12216 label: NFI1 gene_symbol: NFI1 organism: Saccharomyces cerevisiae - id: UniProtKB:O94451 label: pli1 gene_symbol: pli1 organism: Schizosaccharomyces pombe gene_review: genes/SCHPO/pli1/pli1-ai-review.yaml - id: UniProtKB:F4JYG0 label: PIAL2 gene_symbol: PIAL2 organism: Arabidopsis thaliana - id: UniProtKB:A0A6J3SHB9 label: tna gene_symbol: tna organism: Drosophila melanogaster diverged_from_family: false - subfamily_id: PANTHER:PTHR10782:SF68 label: E4 SUMO-PROTEIN LIGASE PIAL1 description: >- Arabidopsis PIAL1, from a Brassicaceae duplication (PTN000081880) together with PIAL2. It is an SP-RING ligase that extends SUMO chains and needs SUMO-modified SCE1 (the plant Ubc9) for full activity. It acts in salt and osmotic stress responses and sulfur metabolism. representative_members: - id: UniProtKB:A0A0A7EPL0 label: PIAL1 gene_symbol: PIAL1 organism: Arabidopsis thaliana diverged_from_family: true divergence_description: >- The mode of ligation differs. PIAL1 and PIAL2 are characterised as SUMO chain-forming ("E4") ligases, not as ligases that transfer single SUMO moieties onto substrates. This is still SUMO ligase activity (GO:0061665): SUMO is transferred to an acceptor lysine that sits on SUMO. The family-level MF and BP terms are therefore correct here. Gene reviews should record chain elongation as the specific activity, and substrate-specific E3 claims made for SIZ1 should not be transferred to PIAL1/PIAL2. - subfamily_id: PANTHER:PTHR10782:SF102 label: E3 SUMO-PROTEIN LIGASE SIZ1 description: >- Plant SIZ1 orthologs (Arabidopsis and rice SIZ1). This is the main plant SUMO E3. It has the SAP, PINIT and SP-RING domains plus a plant-specific PHD domain, and it controls stress, hormone and developmental responses through substrates such as ICE1. representative_members: - id: UniProtKB:Q680Q4 label: SIZ1 gene_symbol: SIZ1 organism: Arabidopsis thaliana gene_review: genes/ARATH/SIZ1/SIZ1-ai-review.yaml - id: UniProtKB:Q6L4L4 label: SIZ1 gene_symbol: SIZ1 organism: Oryza sativa subsp. japonica diverged_from_family: false - subfamily_id: PANTHER:PTHR10782:SF42 label: E3 SUMO-PROTEIN LIGASE SIZ2 description: Rice SIZ2, the grass SIZ1 paralog and a PAINT seed for SUMO ligase activity. representative_members: - id: UniProtKB:Q6ASW7 label: SIZ2 gene_symbol: SIZ2 organism: Oryza sativa subsp. japonica diverged_from_family: false node_assessments: - node_id: PANTHER:PTN000081660 asserted_term: id: GO:0061665 label: SUMO ligase activity evidence: IBD node_taxon: id: NCBITaxon:2759 label: Eukaryota paint_snapshot: '20260528' seeds: - id: UniProtKB:O75925 label: PIAS1 organism: Homo sapiens - id: UniProtKB:O75928 label: PIAS2 organism: Homo sapiens - id: UniProtKB:Q8N2W9 label: PIAS4 organism: Homo sapiens - id: MGI:MGI:1913125 label: Pias1 organism: Mus musculus - id: MGI:MGI:2136940 label: Pias4 organism: Mus musculus - id: FB:FBgn0003612 label: Su(var)2-10 organism: Drosophila melanogaster - id: WB:WBGene00001574 label: gei-17 organism: Caenorhabditis elegans - id: PomBase:SPAC1687.05 label: pli1 organism: Schizosaccharomyces pombe - id: AGI_LocusCode:AT1G08910 label: PIAL1 organism: Arabidopsis thaliana - id: AGI_LocusCode:AT5G41580 label: PIAL2 organism: Arabidopsis thaliana - id: UniProtKB:Q6L4L4 label: SIZ1 organism: Oryza sativa subsp. japonica - id: UniProtKB:Q6ASW7 label: SIZ2 organism: Oryza sativa subsp. japonica - id: CGD:CAL0000192524 label: FGR3 (orf19.11326) organism: Candida albicans assessment: SOUND assessment_reason: >- In the PANTHER 19 tree, PTN000081660 is the family root (Eukaryota speciation). Its seeds span fungi, plants, nematode, insect and vertebrates, so a root placement is the only one that covers them. The mechanism is the shared SP-RING, which binds Ubc9 and activates the E2~SUMO thioester. The four zinc ligands (PIAS1 C351/H353/C374/C377) are conserved in every reviewed member aligned here: PIAS1-4, ZMIZ1/2, Su(var)2-10, GEI-17, yeast Siz1, Pli1, Arabidopsis SIZ1, PIAL1 and PIAL2. No branch therefore shows a catalytic-site loss that would call for an IRD. Two clades inherit the term with weaker support. (1) The bilaterian ZMIZ clade (PTN000081664: ZMIZ1, ZMIZ2, tonalli, miz-1) has no ZMIZ seed. hZimp10 increases AR sumoylation only modestly, and the authors could not conclude that it acts directly as an E3. Gene reviews for ZMIZ1/2 should treat the IBA as non-core, not remove it. (2) PIAL1/PIAL2 are chain-forming ligases. That is a mode of SUMO ligase activity, not a different activity, and both are seeds. supported_by: - reference_id: PMID:11572779 supporting_text: "Siz1 and the related protein Siz2 promote SUMO conjugation to different substrates at different stages of the cell cycle and, together, are required for most SUMO conjugation in yeast." - reference_id: PMID:11583632 supporting_text: "PIAS1 catalyzed the sumoylation of p53 both in U2OS cells and in vitro in a domain-dependent manner." - reference_id: PMID:25475837 supporting_text: "Moreover, the L/A mutation of the SP-RING within GEI-17 drastically diminishes its SUMO E3 activity." - node_id: PANTHER:PTN000081660 asserted_term: id: GO:0016925 label: protein sumoylation evidence: IBD node_taxon: id: NCBITaxon:2759 label: Eukaryota paint_snapshot: '20250902' seeds: - id: SGD:S000002817 label: SIZ1 organism: Saccharomyces cerevisiae - id: SGD:S000005682 label: NFI1 (SIZ2) organism: Saccharomyces cerevisiae - id: PomBase:SPAC1687.05 label: pli1 organism: Schizosaccharomyces pombe - id: AGI_LocusCode:AT5G60410 label: SIZ1 organism: Arabidopsis thaliana - id: AGI_LocusCode:AT1G08910 label: PIAL1 organism: Arabidopsis thaliana - id: UniProtKB:O75925 label: PIAS1 organism: Homo sapiens - id: WB:WBGene00001574 label: gei-17 organism: Caenorhabditis elegans - id: FB:FBgn0003612 label: Su(var)2-10 organism: Drosophila melanogaster - id: UniProtKB:C8V0C1 label: sizA organism: Aspergillus nidulans - id: UniProtKB:Q38DR7 label: Tb09.211.2400 organism: Trypanosoma brucei brucei assessment: SOUND assessment_reason: >- This is the process counterpart of the ligase activity. The ligase performs the conjugation step, so this is a correct participation claim and not a substrate-type over-annotation. The seed set is broad, including Trypanosoma and Aspergillus members, which supports a eukaryotic root placement. The same ZMIZ caveat applies as for GO:0061665. supported_by: - reference_id: PMID:17416732 supporting_text: "SIZ1-dependent sumoylation of ICE1 in protoplasts was moderately induced by cold." - node_id: PANTHER:PTN000081660 asserted_term: id: GO:0005654 label: nucleoplasm evidence: IBD node_taxon: id: NCBITaxon:2759 label: Eukaryota paint_snapshot: '20260528' seeds: - id: AGI_LocusCode:AT5G60410 label: SIZ1 organism: Arabidopsis thaliana - id: FB:FBgn0003612 label: Su(var)2-10 organism: Drosophila melanogaster - id: UniProtKB:O75928 label: PIAS2 organism: Homo sapiens - id: UniProtKB:Q9Y6X2 label: PIAS3 organism: Homo sapiens - id: UniProtKB:Q8N2W9 label: PIAS4 organism: Homo sapiens - id: UniProtKB:Q9ULJ6 label: ZMIZ1 organism: Homo sapiens - id: UniProtKB:Q8NF64 label: ZMIZ2 organism: Homo sapiens - id: UniProtKB:Q586P7 label: Tb927.2.4420 organism: Trypanosoma brucei brucei assessment: SOUND assessment_reason: >- Nuclear localisation, aided by the SAP motif and nuclear localisation signals, is a consistent family feature. Seeds come from both the PIAS and the ZMIZ clades and from plants and trypanosomes. Yeast Siz1 moves to the bud neck in G2/M to sumoylate septins. That adds a second location; it does not contradict the nucleoplasm assertion. - node_id: PANTHER:PTN000081660 asserted_term: id: GO:0000785 label: chromatin evidence: IBD node_taxon: id: NCBITaxon:2759 label: Eukaryota paint_snapshot: '20240205' seeds: - id: FB:FBgn0026160 label: tna organism: Drosophila melanogaster - id: SGD:S000002817 label: SIZ1 organism: Saccharomyces cerevisiae - id: SGD:S000005682 label: NFI1 (SIZ2) organism: Saccharomyces cerevisiae - id: WB:WBGene00001574 label: gei-17 organism: Caenorhabditis elegans assessment: SOUND assessment_reason: >- The seeds sit on both sides of the PIAS/ZMIZ split (gei-17 on one, tonalli on the other) and include budding yeast, so the root placement follows from them. The family deep-research report calls this term over-annotated because Siz1 also sumoylates bud-neck septins. That argument does not hold. An is_active_in chromatin assertion does not claim that chromatin is the only location, and Siz1's best-studied nuclear substrate, PCNA, is sumoylated when it is loaded onto DNA. The SAP DNA-binding motif and the chromatin-level roles of PIAS proteins (heterochromatin and chromosome structure for Su(var)2-10, mitotic chromosomes for GEI-17, Brahma-complex interactions for tonalli) fit chromatin as a site of action across the family. supported_by: - reference_id: PMID:18701921 supporting_text: "During most of the cell cycle, Siz1 is nuclear, with the exception of G2/M phase, when the E3 associates with the bud neck and participates in septin sumoylation" - reference_id: PMID:18031232 supporting_text: "SAP (scaffold attachment factor-A/B/acinus/PIAS) domain capable of interacting with DNA" - node_id: PANTHER:PTN000081664 asserted_term: id: GO:0003713 label: transcription coactivator activity evidence: IBD node_taxon: id: NCBITaxon:33213 label: Bilateria paint_snapshot: '20250411' seeds: - id: UniProtKB:Q9ULJ6 label: ZMIZ1 organism: Homo sapiens - id: UniProtKB:Q8NF64 label: ZMIZ2 organism: Homo sapiens assessment: SOUND assessment_reason: >- PTN000081664 is the bilaterian ZMIZ clade (vertebrate ZMIZ1/2, Drosophila tonalli, C. elegans miz-1), the sister of the PIAS clade below the eumetazoan duplication PTN008310868. Both seeds are vertebrate. The extension to Ecdysozoa is reasonable: tonalli is a trithorax-group gene that interacts genetically with the Brahma remodeling complex and Mediator and is needed for homeotic gene expression, which is consistent with coactivator function. It is untested biochemically. The term does not reach the PIAS clade or non-metazoan members, which is correct. - node_id: PANTHER:PTN001324782 asserted_term: id: GO:0006357 label: regulation of transcription by RNA polymerase II evidence: IBD paint_snapshot: '20250902' seeds: - id: UniProtKB:O75925 label: PIAS1 organism: Homo sapiens - id: UniProtKB:Q9ULJ6 label: ZMIZ1 organism: Homo sapiens - id: UniProtKB:Q8NF64 label: ZMIZ2 organism: Homo sapiens - id: MGI:MGI:1913125 label: Pias1 organism: Mus musculus - id: MGI:MGI:1096566 label: Pias2 organism: Mus musculus - id: MGI:MGI:1913126 label: Pias3 organism: Mus musculus - id: MGI:MGI:2136940 label: Pias4 organism: Mus musculus - id: MGI:MGI:3040693 label: Zmiz1 organism: Mus musculus assessment: SOUND assessment_reason: >- PAINT records no taxon for this node. The unfiltered PANTHER 19 tree places PTN001324782 at the Metazoa-Choanoflagellida speciation, directly above the eumetazoan PIAS/ZMIZ duplication. The seeds come from both paralog groups, so this is the lowest node that covers them. Both groups act as RNA polymerase II coregulators, the PIAS proteins as SUMO E3s and as SAP/SIM-dependent platforms and the ZMIZ proteins as coactivators, so the participation claim is appropriate. Fungal and plant members do not inherit it, which is correct. Choanoflagellate members inherit it without evidence, which is acceptable for a broad regulation term. - node_id: PANTHER:PTN000845825 asserted_term: id: GO:0140416 label: transcription regulator inhibitor activity evidence: IBD node_taxon: id: NCBITaxon:6072 label: Eumetazoa paint_snapshot: '20251212' seeds: - id: UniProtKB:O75925 label: PIAS1 organism: Homo sapiens assessment: SOUND assessment_reason: >- PTN000845825 is the eumetazoan root of the PIAS clade (SF94 assigned here). Below it are the vertebrate PIAS1-4 subfamilies, Su(var)2-10 and GEI-17. The single seed, PIAS1, blocks Stat1 DNA binding. PIAS3 does the same to Stat3, and Su(var)2-10 binds and counteracts activated STAT92E, so inhibition of transcription factors is shared across the vertebrate and insect members. The ZMIZ coactivators are correctly excluded. For GEI-17 the term is plausible but not demonstrated. The term covers inhibition by binding or by post-translational modification. A binding route through the SAP domain is not supported: GEI-17 has no detectable SAP domain, and in PIAS1 the ligase-independent inhibition does not need it anyway, mapping instead to a region around an acidic cluster (PMID:24036127). GEI-17 keeps a PIAS1-like SIM-plus-acidic module at the equivalent position after the SP-RING, so binding through that module is not excluded, though untested. A modification route is also plausible: GEI-17 inhibits formation of piRNA transcription condensates built by the USTC transcription complex in a SUMOylation-dependent way (PMID:40316696), but whether it SUMOylates USTC components directly is not shown in the cached abstract. The gei-17 gene review therefore leaves its IBA UNDECIDED rather than refuting it. Transcription-factor inhibition by PIAS proteins is not limited to STATs (MITF and others), so the activity need not depend on a JAK-STAT pathway. supported_by: - reference_id: PMID:9388184 supporting_text: "PIAS3 blocked the DNA-binding activity of Stat3 and inhibited Stat3-mediated gene activation." - reference_id: PMID:11504941 supporting_text: "dPIAS counteracts the activated STAT92E" - reference_id: PMID:18031232 supporting_text: "PIAS proteins do not operate merely as SUMO E3s, since their co-regulator effects are often independent of their RING finger" - reference_id: PMID:24036127 supporting_text: "PIAS1 with a mutation in the SAP domain retained the inhibitory function in virus-induced IFN transcription" - reference_id: PMID:40316696 supporting_text: "isolated the SUMO E3 ligase GEI-17 as inhibiting and the SUMO protease TOFU-3 as promoting piRNA transcription foci formation" - node_id: PANTHER:PTN000845825 asserted_term: id: GO:0046426 label: negative regulation of receptor signaling pathway via JAK-STAT evidence: IBD node_taxon: id: NCBITaxon:6072 label: Eumetazoa paint_snapshot: '20251212' seeds: - id: UniProtKB:O75925 label: PIAS1 organism: Homo sapiens - id: FB:FBgn0003612 label: Su(var)2-10 organism: Drosophila melanogaster assessment: NEEDS_PRUNING assessment_reason: >- The placement follows from the seeds, PIAS1 (vertebrate) and Su(var)2-10 (insect), whose last common ancestor in this tree is the eumetazoan PIAS node. The JAK-STAT role is well supported in both lineages. The nematode branch is the problem: C. elegans has no JAK, and its STAT STA-1 works through a JAK-independent pathway. GEI-17 (leaf PTN000081832, under the ecdysozoan node PTN000081830) therefore inherits regulation of a receptor-JAK-STAT pathway that its organism lacks. An IRD for the C. elegans/nematode lineage, or a NOT annotation on GEI-17, is recommended. No subfamily is named as affected because SF94 contains both GEI-17 and the valid seed Su(var)2-10; GEI-17 is instead recorded as a member exception on the GO:0046426 term assessment, anchored to this node. supported_by: - reference_id: PMID:9724754 supporting_text: "These results identify PIAS1 as a specific inhibitor of Stat1-mediated gene activation" - reference_id: PMID:28874466 supporting_text: "the absence of both interferon and JAK, the C. elegans STAT homolog STA-1" - reference_id: PMID:28874466 supporting_text: "There is no conserved homolog of the JAK kinases in C. elegans" - node_id: PANTHER:PTN002583825 asserted_term: id: GO:0000122 label: negative regulation of transcription by RNA polymerase II evidence: IBD node_taxon: id: NCBITaxon:117571 label: Euteleostomi paint_snapshot: '20251212' seeds: - id: MGI:MGI:1913125 label: Pias1 organism: Mus musculus - id: MGI:MGI:1913126 label: Pias3 organism: Mus musculus assessment: SOUND assessment_reason: >- PTN002583825 is the euteleostome SF11 node above the tetrapod PIAS1/PIAS3 duplication (PTN004192120). Its seeds are mouse Pias1 and Pias3, so the node is the lowest that covers them. Repression of target genes (STAT, MITF and Sp3, among others) is documented for both paralogs. PIAS1/PIAS3 also activate some promoters, so this is a correct participation term but not the whole story. residue_sites: - site_id: spring_zinc_site label: SP-RING zinc ligands description: >- The four zinc-coordinating residues of the SP-RING (MIZ-type) zinc finger, from UniProt binding features on PIAS1. Mutating C351 abolishes UBE2I binding and almost abolishes PIAS1-promoted p53 sumoylation, while SUMO1 and p53 binding are kept. Pairwise alignment to the PIAS1 SP-RING (this review, Biopython local alignment) shows all four ligands conserved in PIAS2, PIAS3, PIAS4, ZMIZ1 (C758/H760/C781/C784), ZMIZ2 (C616/H618/C639/C642), Su(var)2-10 (Q7KNF5 C341/H343/C364/C367), GEI-17 (C431/H433/C454/C457), yeast Siz1, Pli1, Arabidopsis SIZ1, PIAL1 and PIAL2. No reviewed family member lacks the site, so there is no natural negative control. That is why the strength is CONTRIBUTES and not REQUIRED. anchor: id: UniProtKB:O75925 label: PIAS1 gene_symbol: PIAS1 organism: Homo sapiens anchor_sequence_version: 2 site_source: UNIPROT_FEATURE residues: - position: 351 expected: [C] role: Zn(2+) ligand - position: 353 expected: [H] role: Zn(2+) ligand - position: 374 expected: [C] role: Zn(2+) ligand - position: 377 expected: [C] role: Zn(2+) ligand required_for: - term: id: GO:0061665 label: SUMO ligase activity strength: CONTRIBUTES rationale: >- The SP-RING binds Ubc9 and positions the E2~SUMO thioester for transfer, as RING E3s do. Zinc coordination holds the RING fold together, so mutating the ligands breaks the Ubc9 interface and ligase activity without affecting the separate SUMO- and substrate-binding surfaces. supported_by: - reference_id: PMID:11583632 supporting_text: PIAS1 that was mutated in the RING finger-like domain bound p53 and SUMO-1, but not Ubc9. - reference_id: PMID:11572779 supporting_text: Siz1, Siz2, and the PIAS (protein inhibitor of activated STAT) proteins form a conserved family defined by an unusual RING-related motif. positive_controls: - id: UniProtKB:Q04195 label: SIZ1 gene_symbol: SIZ1 organism: Saccharomyces cerevisiae control_position: 377 control_residue: C - id: UniProtKB:Q94361 label: gei-17 gene_symbol: gei-17 organism: Caenorhabditis elegans control_position: 431 control_residue: C - id: UniProtKB:A0A0A7EPL0 label: PIAL1 gene_symbol: PIAL1 organism: Arabidopsis thaliana control_position: 299 control_residue: C - id: UniProtKB:Q680Q4 label: SIZ1 gene_symbol: SIZ1 organism: Arabidopsis thaliana control_position: 379 control_residue: C term_assessments: - assessed_term: id: GO:0061665 label: SUMO ligase activity scope: FAMILY_WIDE scope_reason: >- Shown directly in fungal, plant, nematode, insect and vertebrate members, and the SP-RING zinc site is intact in every reviewed member. It is a core function for the PIAS clade, the Siz/Pli1 fungal ligases and plant SIZ1/SIZ2/PIAL1/PIAL2. For the ZMIZ clade (SF7, SF38, tonalli/miz-1) it is plausible but only weakly evidenced, so gene reviews there should keep it as non-core. supported_by: - reference_id: PMID:11572779 supporting_text: Siz1 and the related protein Siz2 promote SUMO conjugation to different substrates at different stages of the cell cycle and, together, are required for most SUMO conjugation in yeast. - reference_id: PMID:11583632 supporting_text: PIAS1 catalyzed the sumoylation of p53 both in U2OS cells and in vitro in a domain-dependent manner. - reference_id: PMID:25475837 supporting_text: Moreover, the L/A mutation of the SP-RING within GEI-17 drastically diminishes its SUMO E3 activity. - reference_id: PMID:25415977 supporting_text: We show that PIAL1 and PIAL2 function as SUMO ligases capable of SUMO chain formation - reference_id: PMID:14609956 supporting_text: Based on the experimental design, we were not able to conclude whether hZimp10 is acting directly as an E3 ligase. - reference_id: PMID:18031232 supporting_text: proteins promote SUMOylation in a manner that resembles the action of RING-type ubiquitin E3 ligases - assessed_term: id: GO:0016925 label: protein sumoylation scope: FAMILY_WIDE scope_reason: >- Participation follows directly from the ligase activity, because the ligase performs the conjugation step. The same ZMIZ caveat applies. supported_by: - reference_id: PMID:17416732 supporting_text: SIZ1-dependent sumoylation of ICE1 in protoplasts was moderately induced by cold. - assessed_term: id: GO:0000785 label: chromatin scope: FAMILY_WIDE scope_reason: >- A site of action, not the only location. Yeast Siz1 is nuclear for most of the cell cycle and goes to the bud neck only in G2/M. That reason was used to call the term over-broad, but it adds a location and does not refute chromatin. Do not demote the term to nucleus on that basis. supported_by: - reference_id: PMID:18701921 supporting_text: During most of the cell cycle, Siz1 is nuclear, with the exception of G2/M phase, when the E3 associates with the bud neck and participates in septin sumoylation - reference_id: PMID:18031232 supporting_text: SAP (scaffold attachment factor-A/B/acinus/PIAS) domain capable of interacting with DNA - assessed_term: id: GO:0140416 label: transcription regulator inhibitor activity scope: SUBFAMILY_ONLY applicable_subfamilies: - id: PANTHER:PTHR10782:SF11 label: E3 SUMO-PROTEIN LIGASE PIAS1 - id: PANTHER:PTHR10782:SF10 label: E3 SUMO-PROTEIN LIGASE PIAS3 - id: PANTHER:PTHR10782:SF12 label: E3 SUMO-PROTEIN LIGASE PIAS2 - id: PANTHER:PTHR10782:SF9 label: E3 SUMO-PROTEIN LIGASE PIAS4 - id: PANTHER:PTHR10782:SF101 label: E3 SUMO-PROTEIN LIGASE PIAS1 - id: PANTHER:PTHR10782:SF94 label: SUPPRESSOR OF VARIEGATION 2-10, ISOFORM I scope_reason: >- STAT inhibition (blocking STAT DNA binding) is a metazoan PIAS-clade activity and is often independent of the SP-RING. It does not apply to the ZMIZ coactivators, fungal Siz/Pli1 or plant SIZ1/PIAL, and must never be promoted to family level. supported_by: - reference_id: PMID:9388184 supporting_text: PIAS3 blocked the DNA-binding activity of Stat3 and inhibited Stat3-mediated gene activation. - reference_id: PMID:11504941 supporting_text: dPIAS counteracts the activated STAT92E - reference_id: PMID:18031232 supporting_text: PIAS proteins do not operate merely as SUMO E3s, since their co-regulator effects are often independent of their RING finger - reference_id: PMID:18031232 supporting_text: PIAS proteins were initially named for their ability to interact with STAT proteins and inhibit their activity, but their interactions and functions are not restricted to the STATs. - assessed_term: id: GO:0046426 label: negative regulation of receptor signaling pathway via JAK-STAT scope: SUBFAMILY_ONLY applicable_subfamilies: - id: PANTHER:PTHR10782:SF11 label: E3 SUMO-PROTEIN LIGASE PIAS1 - id: PANTHER:PTHR10782:SF10 label: E3 SUMO-PROTEIN LIGASE PIAS3 - id: PANTHER:PTHR10782:SF12 label: E3 SUMO-PROTEIN LIGASE PIAS2 - id: PANTHER:PTHR10782:SF9 label: E3 SUMO-PROTEIN LIGASE PIAS4 - id: PANTHER:PTHR10782:SF101 label: E3 SUMO-PROTEIN LIGASE PIAS1 - id: PANTHER:PTHR10782:SF94 label: SUPPRESSOR OF VARIEGATION 2-10, ISOFORM I scope_reason: >- Applies to the vertebrate PIAS subfamilies and to Drosophila Su(var)2-10 within SF94. It does not apply to C. elegans GEI-17, also in SF94, because nematodes have no JAK; PANTHER does not split SF94 between the fly and nematode branches, so GEI-17 is carved out as a member exception below rather than by subfamily. member_exceptions: - member: id: UniProtKB:Q94361 label: E3 SUMO-protein ligase gei-17 gene_symbol: gei-17 organism: Caenorhabditis elegans gene_review: genes/worm/gei-17/gei-17-ai-review.yaml exception_reason: >- Negative regulation of a receptor-JAK-STAT pathway presupposes JAK, and C. elegans has no conserved JAK homolog; its STAT STA-1 acts in a JAK-independent pathway. GEI-17 inherits the term from the eumetazoan node PTN000845825 only by descent through the nematode branch, where the pathway is absent. The term should be removed from GEI-17 and an IRD placed on the nematode branch in PAINT. pruned_node_id: PANTHER:PTN000845825 supported_by: - reference_id: PMID:28874466 supporting_text: There is no conserved homolog of the JAK kinases in C. elegans - reference_id: PMID:28874466 supporting_text: the absence of both interferon and JAK, the C. elegans STAT homolog STA-1 supported_by: - reference_id: PMID:9724754 supporting_text: These results identify PIAS1 as a specific inhibitor of Stat1-mediated gene activation - reference_id: PMID:28874466 supporting_text: the absence of both interferon and JAK, the C. elegans STAT homolog STA-1 references: - id: PMID:24036127 title: PIAS1 negatively modulates virus triggered type I IFN signaling by blocking the DNA binding activity of IRF3. - id: PMID:40316696 title: piRNA gene density and SUMOylation organize piRNA transcriptional condensate formation. - id: PMID:11572779 title: An E3-like factor that promotes SUMO conjugation to the yeast septins. - id: PMID:11583632 title: Involvement of PIAS1 in the sumoylation of tumor suppressor p53. - id: PMID:25415977 title: Arabidopsis PIAL1 and 2 promote SUMO chain formation as E4-type SUMO ligases and are involved in stress responses and sulfur metabolism. - id: PMID:14609956 title: hZimp10 is an androgen receptor co-activator and forms a complex with SUMO-1 at replication foci. - id: PMID:35670836 title: 'ZMIZ proteins: partners in transcriptional regulation and risk factors for human disease.' - id: PMID:12466201 title: The Drosophila trithorax group gene tonalli (tna) interacts genetically with the Brahma remodeling complex and encodes an SP-RING finger protein. - id: PMID:9388184 title: Specific inhibition of Stat3 signal transduction by PIAS3. - id: PMID:9724754 title: Inhibition of Stat1-mediated gene activation by PIAS1. - id: PMID:18031232 title: PIAS proteins as regulators of small ubiquitin-related modifier (SUMO) modifications and transcription. - id: PMID:11504941 title: A Drosophila PIAS homologue negatively regulates stat92E. - id: PMID:25475837 title: Dynamic SUMO modification regulates mitotic chromosome assembly and cell cycle progression in Caenorhabditis elegans. - id: PMID:18701921 title: SUMO modification of PCNA is controlled by DNA. - id: PMID:17416732 title: SIZ1-mediated sumoylation of ICE1 controls CBF3/DREB1A expression and freezing tolerance in Arabidopsis. - id: PMID:28874466 title: An Alternative STAT Signaling Pathway Acts in Viral Immunity in Caenorhabditis elegans. - id: file:interpro/panther/panther.obo title: PANTHER official family and subfamily vocabulary review_status: COMPLETE reviewed_by: claude-code review_date: '2026-10-04' notes: >- Tree topology, subfamily assignments and PTN positions come from the PANTHER 19 treeinfo service, queried both filtered to model organisms and unfiltered. The unfiltered tree is needed to see PTN001324782 (Metazoa-Choanoflagellida) and PTN000845825 (eumetazoan PIAS root), which the model-organism view collapses. Seed ids were resolved with the PANTHER organism classification files and UniProt xref queries. PANTHER's family name (ZINC FINGER MIZ DOMAIN-CONTAINING PROTEIN) comes from ZMIZ and does not reflect the family's main activity. Family background (SP-RING ligase acting like a RING E3, SAP DNA-binding domain, coregulator effects often independent of the RING, and STAT interaction as the historical but not the defining activity) follows the Palvimo 2007 review (PMID:18031232, abstract only). The InterPro LLM description ("Protein Inhibitor of Activated STAT") gives too much weight to metazoan STAT biology. Fly Su(var)2-10 is cited as Q7KNF5 to match its gene review; PANTHER's own classification uses A1Z7P5, and both carry SF94. The family deep-research report (OpenScientist) recommended demoting chromatin to nucleus and claimed universal subfamily GO mappings. The chromatin recommendation is rejected here (see the GO:0000785 node and term assessments). Its subfamily GO counts were not re-derived. SP-RING zinc-ligand conservation was checked by pairwise local alignment (BLOSUM62) of UniProt canonical sequences against the PIAS1 SP-RING (residues 301-420). The GEI-17 member exception on GO:0046426 is supported by the C. elegans primary paper (PMID:28874466); the Liongue and Ward 2013 JAK-STAT evolution review (PMID:24058787) does not discuss PIAS proteins or nematode JAK absence, so it is not cited for that exception. A cross-gene briefing on JAK-STAT taxon scope across the STAT, JAK and PIAS families and the C. elegans and Dictyostelium STAT modules is at https://claude.ai/artifact/4MLfbbbWWnLchDvspwdPuM.