PIAS1

Summary

PIAS1 (protein inhibitor of activated STAT 1, HGNC:2752) is a protein-coding gene on chromosome 15q23, encoding E3 SUMO-protein ligase PIAS1 (O75925). Functions as an E3-type small ubiquitin-like modifier (SUMO) ligase, stabilizing the interaction between UBE2I and the substrate, and as a SUMO-tethering factor. It is a selective cancer dependency (DepMap: 16.6% of cell lines).

This gene encodes a member of the protein inhibitor of activated STAT (PIAS) family. PIAS proteins function as SUMO E3 ligases and play important roles in many cellular processes by mediating the sumoylation of target proteins. This protein plays a central role as a transcriptional coregulator of numerous cellular pathways includign the STAT1 and nuclear factor kappaB pathways. Alternate splicing results in multiple transcript variants.

Source: NCBI Gene 8554 — RefSeq curated summary.

At a glance

• GWAS associations: 6
• Clinical variants (ClinVar): 122 total — 1 likely-pathogenic
• Phenotypes (HPO): 1
• Cancer dependency (DepMap): dependent in 16.6% of screened cell lines
• MANE Select transcript: NM_016166

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2752
Approved symbol	PIAS1
Name	protein inhibitor of activated STAT 1
Location	15q23
Locus type	gene with protein product
Status	Approved
Aliases	GBP, GU/RH-II, ZMIZ3
Ensembl gene	ENSG00000033800
Ensembl biotype	protein_coding
OMIM	603566
Entrez	8554

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 8 protein_coding, 3 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000249636, ENST00000545237, ENST00000562190, ENST00000563996, ENST00000564009, ENST00000564915, ENST00000567417, ENST00000611270, ENST00000899735, ENST00000899736, ENST00000899737, ENST00000937336, ENST00000964577, ENST00000964578

RefSeq mRNA: 2 — MANE Select: NM_016166 NM_001320687, NM_016166

CCDS: CCDS45290, CCDS81902

Canonical transcript exons

ENST00000249636 — 14 exons

Exon	Start	End
ENSE00000695831	68142290	68142337
ENSE00000695841	68146566	68146700
ENSE00000695855	68175637	68175767
ENSE00000695857	68176474	68176654
ENSE00000885365	68145816	68145906
ENSE00000885368	68164731	68164804
ENSE00000885369	68173732	68173892
ENSE00000885374	68183630	68183667
ENSE00001197824	68153590	68153695
ENSE00001535807	68054315	68054350
ENSE00003583963	68141946	68142030
ENSE00003603364	68181212	68181354
ENSE00003622483	68086306	68086750
ENSE00003745851	68187542	68193847

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 97.28.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 67.4324 / max 1613.6084, expressed in 1823 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
147378	57.8228	1820
147377	7.5676	1664
147384	1.1104	580
147379	0.4471	198
147382	0.3388	155
147381	0.1255	34
147376	0.0203	7

Top tissues by expression

300 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	97.28	gold quality
oocyte	CL:0000023	96.33	gold quality
seminal vesicle	UBERON:0000998	95.96	gold quality
nipple	UBERON:0002030	95.90	gold quality
caput epididymis	UBERON:0004358	95.41	gold quality
cauda epididymis	UBERON:0004360	94.89	gold quality
bone marrow cell	CL:0002092	94.86	gold quality
cardia of stomach	UBERON:0001162	94.85	gold quality
trabecular bone tissue	UBERON:0002483	94.76	gold quality
calcaneal tendon	UBERON:0003701	94.73	gold quality
buccal mucosa cell	CL:0002336	94.65	gold quality
bone marrow	UBERON:0002371	94.55	gold quality
blood	UBERON:0000178	94.15	gold quality
pylorus	UBERON:0001166	94.05	gold quality
corpus epididymis	UBERON:0004359	93.80	gold quality
urethra	UBERON:0000057	93.62	gold quality
vena cava	UBERON:0004087	93.45	gold quality
penis	UBERON:0000989	92.73	gold quality
tendon	UBERON:0000043	92.70	gold quality
endothelial cell	CL:0000115	92.46	silver quality
lower esophagus mucosa	UBERON:0035834	92.38	gold quality
superior surface of tongue	UBERON:0007371	92.35	gold quality
lower lobe of lung	UBERON:0008949	92.19	gold quality
adult organism	UBERON:0007023	92.18	gold quality
trigeminal ganglion	UBERON:0001675	92.13	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	92.06	gold quality
monocyte	CL:0000576	91.91	gold quality
leukocyte	CL:0000738	91.85	gold quality
mononuclear cell	CL:0000842	91.84	gold quality
colonic epithelium	UBERON:0000397	91.74	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-9388	yes	6.36
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

6 targets.

Target	Regulation
CYP17A1	Unknown
FABP2	Activation
MUC1	Repression
PRMT1	Repression
SI	Activation
STAT1	Unknown

Upstream regulators (CollecTRI, top): AIRE, AR, ESR1, GATA4, KLF1, KLF5, MYC, MYOG, NCOA3, NFKB, NR1H2, NR2F1, NR5A1, SIM2, STAT1, TFCP2, ZNF451

miRNA regulators (miRDB)

217 targeting PIAS1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 16.6% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• novel function of PIAS1 in the induction of JNK-dependent apoptosis, independent of the previously known inhibitory activity of PIAS1 in STAT-mediated gene activation. (PMID:11451946)
• protein inhibitor of activated Stat1 (PIAS1) interacts with the tetramerization and C-terminal regulatory domains of p53 in yeast two-hybrid analyses (PMID:11788578)
• Protein inhibitors of activated STAT resemble scaffold attachment factors and function as interacting nuclear receptor coregulators. (PMID:11877418)
• PIAS1 and PIASxalpha modulate the AR-dependent transactivation, which, at least in part, can be attributed to their SUMO-E3 activity toward AR. (PMID:12177000)
• PIAS1 has a role in sumoylation of MDM2 in the cell nucleus (PMID:12393906)
• found to strongly stimulate sumoylation of STAT1 at Lys703; results suggest a negative regulatory function for sumoylation. (PMID:12855578)
• PIAS1 interacts with the N-terminal domain of human mineralocorticoid receptor and represses its ligand-dependent transcription. (PMID:14500761)
• three-dimensional structure and its binding duality are discussed in conjunction with the biological functions of PIAS1 as a SUMO ligase (PMID:15133049)
• GATA4 is a SUMO-1-targeted transcription factor and together with PIAS1 is a potent regulator of cardiac gene activity (PMID:15337742)
• PIAS1 is a checkpoint regulator which affects exit from G1 and G2 by sumoylation of p73. (PMID:15572666)
• PIAS1 interacts with DNA cross-link repair SNM1A in nuclear focus formation. (PMID:15572677)
• data support a physiological role of Ubc9 and PIAS1 as transcriptional coactivators in COUP-TFI-mediated CYP11B2 transcription (PMID:15611122)
• Results suggest that recombinant human interleukin-12 upregulates STAT-1 expression and that increased expression may be dose dependent. (PMID:15901746)
• PIAS1 modulates transcriptional activation of smooth muscle cells marker genes through cooperative interactions with both serum response factor and class I basic helix-loop-helix proteins proteins. (PMID:16135793)
• Pias1 binds to and sumoylates metabotropic glutamate receptor 8 (PMID:16144832)
• In this study, we demonstrate that MEF2A undergoes sumoylation primarily at a single lysine residue (K395) both in vitro and in vivo. We also show that the nuclear E3 ligase, PIAS1, promotes sumoylation of MEF2A. (PMID:16563226)
• PIAS1 is required for the appropriate localization and retention of Msx1 at the nuclear periphery in myoblast cells. (PMID:16600910)
• TGF-beta rapidly suppresses IFN-gamma-driven STAT1 signaling by reducing DNA binding via promotion of STAT1–PIAS1 interactions and not inhibition of STAT1 activation. (PMID:17371985)
• These results suggest that KyoT2 is a substrate of SUMO modification catalyzed by PIAS1, and that SUMOylation may modulate the transcriptional repression effect of KyoT2 on the Notch/RBP-J signaling pathway [Kyot2]. (PMID:17509614)
• PIASy cooperates with PIAS1 to down-regulate the specificity and magnitude of NF-kappa B/STAT1-mediated gene activation. (PMID:17606919)
• the transcriptional repressor activity of ZNF133 is regulated by both the KRAB domain and the zinc finger motifs, and that the repressive effect by zinc finger motifs is mediated by PIAS1 (PMID:17934332)
• The data show that HCV NS3/4a is able to block the Jak-Stat signaling pathway at the stage of Stat-1 serine 727 phosphorylation. (PMID:18190974)
• PIAS1 staining of the colon cancer tissue microarrays indicated a strong correlation of normal colon cells, and adenomas, with high expression of both PIAS1 and IRF-1 (PMID:19288270)
• FOXL2 interacts with PIAS1 and UBC9, and sumoylated in both human and mouse (PMID:20209145)
• Data show that regulation of SATB1 sumoylation and caspase cleavage is controlled by SATB1 phosphorylation; specifically, PIAS1 interaction with SATB1 is inhibited by phosphorylation. (PMID:20351170)
• Pias1-dependent SUMOylation influences Gli protein activity (PMID:20711444)
• PIAS1 is a common partner for two cancer-related nuclear factors, c-Myb and FLASH. (PMID:21338522)
• Ubc9 and PIAS1 potentiated SF-1-mediated transactivation of human CYP17, CYP11A1, and CYP11B1 but not CYP11B2 promoters. (PMID:21467194)
• PIAS1 determines the level of JNK activity in human endometrial stromal cells , couples ROS signaling to the SUMO pathway, and promotes oxidative cell death. (PMID:21676946)
• PIAS1 negatively regulates ubiquitination of Msx1 homeoprotein independent of its SUMO ligase activity. (PMID:21717107)
• There are differences in the PIAS3 expression from different stages of gastric precancerous conditions/lesions to GC, which may reveal a close relationship between expression reduction or loss of PIAS3 and gastric tumorigenesis. (PMID:21925039)
• PIAS1 promotes SUMOylation of AIB1 and represses its transcriptional activity. (PMID:22283414)
• The data reveal an important new role for PIAS1 in the regulation of cell proliferation in prostate cancer. (PMID:22449952)
• PIAS1 is a SUMO ligase for GATA4 that differentially regulates GATA4 transcriptional activity independent of SUMO ligase activity and GATA4 sumoylation. (PMID:22539995)
• data suggest that PIAS1 may function as a tumor suppressor to regulate gastric cancer cell metastasis by targeting the MAPK signaling pathway (PMID:22972521)
• Data suggest that the pro-apoptotic protein Daxx specifically interacts with one or more substrates SUMOylated by PIAS1 and this interaction leads to apoptosis following UV irradiation. (PMID:22976298)
• MAPK-activated protein kinase-2 limits endothelial inflammation via the PIAS1 S522 phosphorylation-mediated increase in PIAS1 transrepression and SUMO ligase activity. (PMID:23202365)
• Levels of STAT1 andor the protein expression of its negative regulators, PIAS1 and SOCS3, may be a good predictor of hepatitis C virus response to therapy (PMID:23472246)
• Further study indicated that PIAS1 interacted with IRF3 and inhibited the DNA binding activity of IRF3. (PMID:24036127)
• Smad2 and PIAS1 proteins were significantly upregulated resulting in dramatically increased interactions between Smad2/4 and PIAS1 in the presence of zinc. (PMID:24052079)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	pias1a	ENSDARG00000036094
danio_rerio	pias1b	ENSDARG00000062445
mus_musculus	Pias1	ENSMUSG00000032405
rattus_norvegicus	Pias1	ENSRNOG00000034272
drosophila_melanogaster	Su(var)2-10	FBGN0003612

Paralogs (5): PIAS2 (ENSG00000078043), PIAS4 (ENSG00000105229), ZMIZ1 (ENSG00000108175), ZMIZ2 (ENSG00000122515), PIAS3 (ENSG00000131788)

Protein

Protein identifiers

E3 SUMO-protein ligase PIAS1 — O75925 (reviewed: O75925)

Alternative names: DEAD/H box-binding protein 1, E3 SUMO-protein transferase PIAS1, Gu-binding protein, Protein inhibitor of activated STAT protein 1, RNA helicase II-binding protein

All UniProt accessions (4): O75925, H3BS65, H3BSI8, H3BUL7

UniProt curated annotations — full annotation on UniProt →

Function. Functions as an E3-type small ubiquitin-like modifier (SUMO) ligase, stabilizing the interaction between UBE2I and the substrate, and as a SUMO-tethering factor. Catalyzes sumoylation of various proteins, such as CEBPB, MRE11, MTA1, PTK2, PML and ZNF76. Plays a crucial role as a transcriptional coregulation in various cellular pathways, including the STAT pathway, the p53 pathway and the steroid hormone signaling pathway. In vitro, binds A/T-rich DNA. The effects of this transcriptional coregulation, transactivation or silencing, may vary depending upon the biological context. Mediates sumoylation of MRE11, stabilizing MRE11 on chromatin during end resection. Sumoylates PML (at ‘Lys-65’ and ‘Lys-160’) and PML-RAR and promotes their ubiquitin-mediated degradation. PIAS1-mediated sumoylation of PML promotes its interaction with CSNK2A1/CK2 which in turn promotes PML phosphorylation and degradation. Enhances the sumoylation of MTA1 and may participate in its paralog-selective sumoylation. Plays a dynamic role in adipogenesis by promoting the SUMOylation and degradation of CEBPB. Mediates the nuclear mobility and localization of MSX1 to the nuclear periphery, whereby MSX1 is brought into the proximity of target myoblast differentiation factor genes. Also required for the binding of MSX1 to the core enhancer region in target gene promoter regions, independent of its sumoylation activity. Capable of binding to the core enhancer region TAAT box in the MYOD1 gene promoter. (Microbial infection) Restricts Epstein-Barr virus (EBV) lytic replication by acting as an inhibitor for transcription factors involved in lytic gene expression. The virus can use apoptotic caspases to antagonize PIAS1-mediated restriction and express its lytic genes.

Subunit / interactions. Interacts with NCOA2 and AR. Interacts with NR2C1; the interaction promotes its sumoylation. Interacts with DDX21, CSRP2, AXIN1, JUN, UBE2I, SUMO1, SATB2, PLAG1, TP53 and STAT1 (dimer), following IFNA1-stimulation. Interacts with SP3 (preferentially when SUMO-modified). Interacts with KLF8; the interaction results in SUMO ligation and repression of KLF8 transcriptional activity and of its cell cycle progression into G(1) phase. Interacts with CHUK/IKKA; this interaction induces PIAS1 phosphorylation. Interacts with PTK2/FAK1; the interaction promotes its sumoylation. Interacts with DDX5. Interacts with PML. Interacts with MTA1. Interacts with SUMO1P1/SUMO5. Interacts with PRDM1/Blimp-1. Interacts (via N-terminus) with MSX1 (via C-terminus); the interaction is required for the localization of both proteins to the nuclear periphery and specific binding of MSX1 to the core enhancer region in target gene promoters. (Microbial infection) Interacts with ebolavirus VP35; this interaction mediates the sumoylation of IRF7 and contributes to the viral inhibition of IFN-type I production.

Subcellular location. Nucleus. Nucleus speckle. PML body. Cytoplasm. Cytoskeleton.

Tissue specificity. Expressed in numerous tissues with highest level in testis.

Post-translational modifications. Sumoylated.

Domain organisation. The LXXLL motif is a transcriptional coregulator signature. The SP-RING-type domain is required for promoting EKLF sumoylation.

Pathway. Protein modification; protein sumoylation.

Similarity. Belongs to the PIAS family.

Isoforms (3)

UniProt ID	Names	Canonical?
O75925-1	1	yes
O75925-2	2
O75925-3	3

RefSeq proteins (2): NP_001307616, NP_057250* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003034	SAP_dom	Domain
IPR004181	Znf_MIZ	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR023321	PINIT	Domain
IPR036361	SAP_dom_sf	Homologous_superfamily
IPR038654	PINIT_sf	Homologous_superfamily

Pfam: PF02891, PF14324

UniProt features (55 total): modified residue 10, cross-link 6, region of interest 5, binding site 4, repeat 4, mutagenesis site 4, helix 4, short sequence motif 3, splice variant 3, sequence conflict 3, compositionally biased region 2, domain 2, site 2, initiator methionine 1, chain 1, zinc finger region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
1V66	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75925-F1	69.20	0.45

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (2): 100 (cleavage; by caspase-6 and -8); 433 (cleavage; by caspase-3, -6, and -8)

Ligand- & substrate-binding residues (4): 351; 353; 374; 377

Post-translational modifications (16): 2, 467, 468, 483, 485, 487, 488, 503, 510, 522, 40, 46, 137, 238, 453, 493

Mutagenesis-validated functional residues (4):

Position	Phenotype
100	completely blocks cleavage by caspase-3, -6, and -8 and dramatic suppression of ebv dna replication; when associated wit
148	no effect on cleavages by caspase-6 and -8.
351	loss of ube2i-binding; almost complete loss of promotion of tp53 sumoylation; no loss of sumo1- and tp53-binding.
433	completely blocks cleavage by caspase-3, -6, and -8 and dramatic suppression of ebv dna replication; when associated wit

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-3108214	SUMOylation of DNA damage response and repair proteins
R-HSA-3232118	SUMOylation of transcription factors
R-HSA-3232142	SUMOylation of ubiquitinylation proteins
R-HSA-3899300	SUMOylation of transcription cofactors
R-HSA-4090294	SUMOylation of intracellular receptors
R-HSA-4551638	SUMOylation of chromatin organization proteins
R-HSA-5696395	Formation of Incision Complex in GG-NER
R-HSA-877312	Regulation of IFNG signaling

MSigDB gene sets: 370 (showing top): REACTOME_FORMATION_OF_INCISION_COMPLEX_IN_GG_NER, RRAGTTGT_UNKNOWN, GOBP_REGULATION_OF_PROTEASOMAL_UBIQUITIN_DEPENDENT_PROTEIN_CATABOLIC_PROCESS, GOBP_COGNITION, GOBP_BEHAVIOR, AMIT_DELAYED_EARLY_GENES, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_REGULATION_OF_SMOOTH_MUSCLE_CELL_DIFFERENTIATION, GOBP_POSITIVE_REGULATION_OF_MUSCLE_CELL_DIFFERENTIATION, GOBP_SMOOTH_MUSCLE_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_PROTEIN_SUMOYLATION, GOBP_ASSOCIATIVE_LEARNING, GOBP_POSITIVE_REGULATION_OF_DNA_TEMPLATED_TRANSCRIPTION_INITIATION, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP

GO Biological Process (22): G1/S transition of mitotic cell cycle (GO:0000082), negative regulation of transcription by RNA polymerase II (GO:0000122), regulation of transcription by RNA polymerase II (GO:0006357), DNA damage response (GO:0006974), cell surface receptor signaling pathway via JAK-STAT (GO:0007259), spermatogenesis (GO:0007283), visual learning (GO:0008542), protein sumoylation (GO:0016925), positive regulation of proteasomal ubiquitin-dependent protein catabolic process (GO:0032436), positive regulation of protein sumoylation (GO:0033235), regulation of cell population proliferation (GO:0042127), negative regulation of apoptotic process (GO:0043066), fat cell differentiation (GO:0045444), positive regulation of transcription by RNA polymerase II (GO:0045944), positive regulation of smooth muscle cell differentiation (GO:0051152), positive regulation of transcription initiation by RNA polymerase II (GO:0060261), protein-DNA complex assembly (GO:0065004), positive regulation of protein localization to cell periphery (GO:1904377), double-strand break repair via homologous recombination (GO:0000724), DNA double-strand break processing (GO:0000729), positive regulation of DNA-templated transcription (GO:0045893), regulation of macromolecule metabolic process (GO:0060255)

GO Molecular Function (14): transcription cis-regulatory region binding (GO:0000976), transcription coregulator activity (GO:0003712), transcription corepressor activity (GO:0003714), zinc ion binding (GO:0008270), SUMO transferase activity (GO:0019789), enzyme binding (GO:0019899), protein domain specific binding (GO:0019904), ubiquitin protein ligase binding (GO:0031625), SUMO ligase activity (GO:0061665), DNA-binding transcription factor binding (GO:0140297), DNA binding (GO:0003677), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (11): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoskeleton (GO:0005856), PML body (GO:0016605), nuclear speck (GO:0016607), nuclear periphery (GO:0034399), glutamatergic synapse (GO:0098978), presynaptic cytosol (GO:0099523), postsynaptic cytosol (GO:0099524), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
SUMO E3 ligases SUMOylate target proteins	6
Global Genome Nucleotide Excision Repair (GG-NER)	1
Interferon gamma signaling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
transcription by RNA polymerase II	3
regulation of transcription by RNA polymerase II	2
negative regulation of DNA-templated transcription	2
double-strand break repair	2
protein binding	2
nuclear lumen	2
cytosol	2
mitotic cell cycle	1
mitotic cell cycle phase transition	1
cell cycle G1/S phase transition	1
regulation of DNA-templated transcription	1
cellular response to stress	1
cell surface receptor signaling pathway via STAT	1
developmental process involved in reproduction	1
male gamete generation	1
visual behavior	1
associative learning	1
peptidyl-lysine modification	1
protein modification by small protein conjugation	1
regulation of proteasomal ubiquitin-dependent protein catabolic process	1
proteasome-mediated ubiquitin-dependent protein catabolic process	1
positive regulation of proteasomal protein catabolic process	1
positive regulation of ubiquitin-dependent protein catabolic process	1
protein sumoylation	1
regulation of protein sumoylation	1
positive regulation of protein modification by small protein conjugation or removal	1
cell population proliferation	1
regulation of cellular process	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
cell differentiation	1
positive regulation of DNA-templated transcription	1
smooth muscle cell differentiation	1
positive regulation of muscle cell differentiation	1
regulation of smooth muscle cell differentiation	1
transcription initiation at RNA polymerase II promoter	1
positive regulation of transcription by RNA polymerase II	1
regulation of transcription initiation by RNA polymerase II	1

Protein interactions and networks

STRING

2190 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PIAS1	UBE2I	P50550	995
PIAS1	STAT1	P42224	994
PIAS1	SUMO2	P55855	939
PIAS1	SUMO1	P55856	935
PIAS1	SAE1	Q9UBE0	850
PIAS1	STAT3	P40763	849
PIAS1	RNF4	P78317	789
PIAS1	RNF8	O76064	741
PIAS1	RNF168	Q8IYW5	733
PIAS1	SENP1	Q9P0U3	732
PIAS1	BRCA1	P38398	730
PIAS1	UBA2	Q9UBT2	715
PIAS1	FOXA1	P55317	708
PIAS1	SRSF1	Q07955	700
PIAS1	DAXX	Q9UER7	690

IntAct

257 interactions, top by confidence:

A	B	Type	Score
PIAS1	HTT	psi-mi:“MI:0915”(physical association)	0.670
PIAS1	ATXN1	psi-mi:“MI:0915”(physical association)	0.670
A2M	PIAS1	psi-mi:“MI:0915”(physical association)	0.560
PIAS1	APBB2	psi-mi:“MI:0915”(physical association)	0.560
PIAS1	ASPA	psi-mi:“MI:0915”(physical association)	0.560
ERCC8	PIAS1	psi-mi:“MI:0915”(physical association)	0.560
DMWD	PIAS1	psi-mi:“MI:0915”(physical association)	0.560
	PIAS1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (526): PIAS1 (Two-hybrid), PIAS1 (Two-hybrid), PIAS1 (Two-hybrid), ZNF451 (Co-localization), PIAS1 (Reconstituted Complex), UBE2I (Reconstituted Complex), UBE2I (Reconstituted Complex), PIAS1 (Biochemical Activity), UBE2I (Reconstituted Complex), SUMO1 (Reconstituted Complex), SUMO2 (Reconstituted Complex), PIAS1 (Reconstituted Complex), UBE2I (Reconstituted Complex), PIAS1 (Biochemical Activity), PIAS1 (Reconstituted Complex)

ESM2 similar proteins: A0A1D5PRR9, A0A3Q0KHE7, A0JMR6, A6QNM3, B0V2S2, B4KA23, B4LVS8, F7BJB9, I3XHK1, O14830, O75925, O88907, P35761, P54350, P59997, P79457, Q0V842, Q14149, Q14191, Q1LWH4, Q4KLY6, Q4R945, Q58DC8, Q5QJC2, Q5RGE5, Q5U263, Q5ZLG9, Q62986, Q68FF0, Q6INA9, Q6NSI8, Q6ZEZ5, Q6ZMT4, Q7ZXF1, Q80Z32, Q86DA5, Q8C0M0, Q8C5W4, Q8C7W7, Q8GT06

Diamond homologs: F1R4C4, F4JYG0, O54714, O70260, O75925, O75928, O88907, Q04195, Q12216, Q680Q4, Q6ASW7, Q6AZ28, Q6L4L4, Q6P1E1, Q8C5D8, Q8CIE2, Q8N2W9, Q8NF64, Q94361, Q9JM05, Q9ULJ6, Q9Y6X2, A0A0A7EPL0, Q8BLG0

SIGNOR signaling

23 interactions.

A	Effect	B	Mechanism
PIAS1	down-regulates	STAT1	binding
PIAS1	up-regulates	SMAD4	sumoylation
PIAS1	up-regulates	DDX5	sumoylation
PIAS1	down-regulates	FHL1	sumoylation
PIAS1	up-regulates	RPA2	sumoylation
PIAS1	up-regulates	TP53BP1	sumoylation
CSNK2A1	up-regulates	PIAS1	phosphorylation
PIAS1	up-regulates	PRDM1	sumoylation
MAPKAPK2	up-regulates	PIAS1	phosphorylation
NDN	“down-regulates quantity by destabilization”	PIAS1	binding
PRKAA1	“up-regulates activity”	PIAS1	phosphorylation
PIAS1	“down-regulates activity”	SATB2	sumoylation
HECTD2	“down-regulates quantity by destabilization”	PIAS1	polyubiquitination
CHUK	“up-regulates activity”	PIAS1	phosphorylation
PIAS1	“up-regulates activity”	AKT1	sumoylation
PIAS1	“up-regulates activity”	AKT	sumoylation
GSK3B	“down-regulates quantity by destabilization”	PIAS1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 89 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
adult locomotory behavior	5	17.7×	3e-03
double-strand break repair	5	11.9×	9e-03
negative regulation of translation	5	11.5×	9e-03
negative regulation of neuron apoptotic process	8	10.4×	1e-03
positive regulation of angiogenesis	6	8.2×	1e-02
negative regulation of gene expression	8	6.5×	7e-03
mRNA processing	7	6.5×	1e-02
nervous system development	9	4.9×	1e-02

Disease & clinical

Clinical variants and AI predictions

ClinVar

122 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	61
Likely benign	24
Benign	23

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
548644	NM_016166.3(PIAS1):c.317C>T (p.Ser106Leu)	Likely pathogenic

SpliceAI

3861 predictions. Top by Δscore:

Variant	Effect	Δscore
15:68054347:AAAGG:A	donor_loss	1.0000
15:68054349:AGGT:A	donor_loss	1.0000
15:68054351:GTA:G	donor_loss	1.0000
15:68054352:T:G	donor_loss	1.0000
15:68085228:A:AG	acceptor_gain	1.0000
15:68086303:A:AG	acceptor_gain	1.0000
15:68086304:A:G	acceptor_gain	1.0000
15:68086305:GCAA:G	acceptor_gain	1.0000
15:68086308:A:G	acceptor_gain	1.0000
15:68141944:A:AG	acceptor_gain	1.0000
15:68141945:G:GG	acceptor_gain	1.0000
15:68142031:G:GG	donor_gain	1.0000
15:68145811:TTTA:T	acceptor_loss	1.0000
15:68145813:TA:T	acceptor_loss	1.0000
15:68145907:G:GG	donor_gain	1.0000
15:68146558:A:AG	acceptor_gain	1.0000
15:68146559:T:G	acceptor_gain	1.0000
15:68146560:TTTTA:T	acceptor_loss	1.0000
15:68146561:TTTA:T	acceptor_loss	1.0000
15:68146563:TAG:T	acceptor_loss	1.0000
15:68146564:A:AG	acceptor_gain	1.0000
15:68146564:AG:A	acceptor_gain	1.0000
15:68146564:AGG:A	acceptor_gain	1.0000
15:68146565:G:GA	acceptor_gain	1.0000
15:68146565:GG:G	acceptor_gain	1.0000
15:68146565:GGG:G	acceptor_gain	1.0000
15:68146565:GGGT:G	acceptor_gain	1.0000
15:68146565:GGGTT:G	acceptor_gain	1.0000
15:68146696:GAAGA:G	donor_gain	1.0000
15:68146697:AAGA:A	donor_gain	1.0000

AlphaMissense

4265 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:68086313:T:A	V11D	1.000
15:68086322:T:C	L14P	1.000
15:68086325:G:C	R15T	1.000
15:68086325:G:T	R15I	1.000
15:68086326:A:C	R15S	1.000
15:68086326:A:T	R15S	1.000
15:68086331:C:T	S17F	1.000
15:68086333:G:A	E18K	1.000
15:68086334:A:T	E18V	1.000
15:68086337:T:A	L19H	1.000
15:68086337:T:C	L19P	1.000
15:68086346:T:A	L22Q	1.000
15:68086346:T:C	L22P	1.000
15:68086346:T:G	L22R	1.000
15:68086349:T:C	L23S	1.000
15:68086349:T:G	L23W	1.000
15:68086375:G:A	G32R	1.000
15:68086375:G:C	G32R	1.000
15:68086376:G:A	G32E	1.000
15:68086376:G:T	G32V	1.000
15:68086381:A:C	K34Q	1.000
15:68086381:A:G	K34E	1.000
15:68086382:A:T	K34I	1.000
15:68086383:A:C	K34N	1.000
15:68086383:A:T	K34N	1.000
15:68086391:T:A	L37H	1.000
15:68086391:T:C	L37P	1.000
15:68086394:T:C	L38P	1.000
15:68086403:C:A	A41D	1.000
15:68086460:T:C	L60P	1.000

dbSNP variants (sampled 300 via entrez): RS1000041049 (15:68058185 A>C,G), RS1000047197 (15:68128880 G>C), RS1000049113 (15:68169265 A>T), RS1000061510 (15:68153132 A>G), RS1000068296 (15:68180523 CTTGTT>C), RS1000105884 (15:68056563 T>C), RS1000133508 (15:68109962 CTTAAAT>C), RS1000141961 (15:68179855 G>T), RS1000191319 (15:68091429 A>G,T), RS1000195193 (15:68088785 A>G,T), RS1000214320 (15:68125750 GAGTAC>G), RS1000240249 (15:68146889 GC>G), RS1000255332 (15:68176085 A>C,G), RS1000256595 (15:68156379 A>G,T), RS1000260447 (15:68176729 A>G)

Disease associations

OMIM: gene MIM:603566 | disease phenotypes: MIM:256100

GenCC curated gene-disease

Mondo (1): nephronophthisis (MONDO:0019005)

Orphanet (1): Nephronophthisis (Orphanet:655)

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0000090	Nephronophthisis

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST001850_6	Major depressive disorder	3.000000e-07
GCST006479_57	Diverticular disease	3.000000e-07
GCST006630_2	Diastolic blood pressure	4.000000e-10
GCST007280_1	Number of twin births	3.000000e-08
GCST010396_59	Gut microbiota (bacterial taxa, hurdle binary method)	8.000000e-06
GCST90014033_63	Haemorrhoidal disease	1.000000e-09

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0009959	diverticular disease
EFO:0006336	diastolic blood pressure
EFO:0009439	multiple births measurement
EFO:0007874	gut microbiome measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

54 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
trichostatin A	decreases expression, affects binding, decreases reaction, increases reaction, increases sumoylation (+1 more)	4
Valproic Acid	affects cotreatment, decreases expression	4
Acetaminophen	decreases expression, increases expression	3
bisphenol S	decreases methylation, affects cotreatment, decreases expression	2
Arsenic	affects methylation, decreases expression	2
Benzo(a)pyrene	increases methylation, affects methylation	2
Cyclosporine	decreases expression, increases expression	2
Cadmium Chloride	decreases expression, increases abundance	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
bisphenol F	decreases methylation	1
TAK-243	increases sumoylation	1
methylmercuric chloride	decreases expression	1
oxybenzone	increases expression	1
bisphenol A	decreases methylation	1
arsenite	affects binding, increases reaction	1
sodium arsenite	decreases expression	1
butyraldehyde	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
coumarin	decreases phosphorylation	1
beta-methylcholine	affects expression	1
testosterone-3-carboxymethyloxime-bovine serum albumin conjugate	decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
motexafin gadolinium	affects reaction, increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	decreases expression, affects cotreatment	1
jinfukang	decreases expression	1
Arsenic Trioxide	increases degradation, increases reaction	1
Air Pollutants	increases abundance, decreases expression	1

Cellosaurus cell lines

4 cell lines: 3 cancer cell line, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D8SG	Ubigene HCT 116 PIAS1 KO	Cancer cell line	Male
CVCL_D9MY	Ubigene HEK293 PIAS1 KO	Transformed cell line	Female
CVCL_E0KB	Ubigene HeLa PIAS1 KO	Cancer cell line	Female
CVCL_TD42	HAP1 PIAS1 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

6 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT01022957	Not specified	COMPLETED	Nephronophthisis : Clinical and Genetic Study
NCT01401998	Not specified	RECRUITING	ARPKD Database Study
NCT04874909	Not specified	COMPLETED	Classification, Functional Stratification and Biomarkers in Ciliopathy (CILLICORIRCM)
NCT05286632	Not specified	COMPLETED	KidneYou - Innovative Digital Therapy
NCT06065852	Not specified	RECRUITING	National Registry of Rare Kidney Diseases
NCT06648044	Not specified	RECRUITING	Research of Therapeutic Targets in the Frame of Nephronophthisis and Renal Associated Ciliopathies