PIAS4

Summary

PIAS4 (protein inhibitor of activated STAT 4, HGNC:17002) is a protein-coding gene on chromosome 19p13.3, encoding E3 SUMO-protein ligase PIAS4 (Q8N2W9). 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.

Enables SUMO ligase activity and ubiquitin protein ligase binding activity. Involved in negative regulation of protein localization to chromatin; protein sumoylation; and regulation of primary metabolic process. Located in cytoplasm and nucleus.

Source: NCBI Gene 51588 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 100 total
• Druggable target: yes
• MANE Select transcript: NM_015897

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17002
Approved symbol	PIAS4
Name	protein inhibitor of activated STAT 4
Location	19p13.3
Locus type	gene with protein product
Status	Approved
Aliases	Piasg, PIASY, FLJ12419, ZMIZ6
Ensembl gene	ENSG00000105229
Ensembl biotype	protein_coding
OMIM	605989
Entrez	51588

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 7 protein_coding, 3 protein_coding_CDS_not_defined, 2 retained_intron

ENST00000262971, ENST00000593518, ENST00000596144, ENST00000599999, ENST00000600566, ENST00000601439, ENST00000862888, ENST00000862889, ENST00000932794, ENST00000932795, ENST00000963735, ENST00000963736

RefSeq mRNA: 1 — MANE Select: NM_015897 NM_015897

CCDS: CCDS12118

Canonical transcript exons

ENST00000262971 — 11 exons

Exon	Start	End
ENSE00000663982	4033420	4033580
ENSE00000894812	4033100	4033173
ENSE00000894813	4028931	4029036
ENSE00000894814	4028720	4028848
ENSE00000951510	4037374	4037504
ENSE00001265000	4037616	4039386
ENSE00003128359	4007736	4007787
ENSE00003483786	4012923	4013349
ENSE00003563902	4028146	4028187
ENSE00003590481	4024036	4024120
ENSE00003614065	4028510	4028600

Expression profiles

Bgee: expression breadth ubiquitous, 227 present calls, max score 92.23.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 17.4362 / max 139.3853, expressed in 1806 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
173259	16.7088	1805
173258	0.7274	448

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left testis	UBERON:0004533	92.23	gold quality
right testis	UBERON:0004534	92.15	gold quality
testis	UBERON:0000473	90.30	gold quality
cortical plate	UBERON:0005343	88.59	gold quality
right hemisphere of cerebellum	UBERON:0014890	88.35	gold quality
stromal cell of endometrium	CL:0002255	88.08	gold quality
oocyte	CL:0000023	87.87	gold quality
cerebellar hemisphere	UBERON:0002245	87.67	gold quality
cerebellar cortex	UBERON:0002129	87.49	gold quality
sural nerve	UBERON:0015488	87.25	gold quality
islet of Langerhans	UBERON:0000006	86.44	gold quality
hindlimb stylopod muscle	UBERON:0004252	85.67	gold quality
cerebellum	UBERON:0002037	85.49	gold quality
muscle layer of sigmoid colon	UBERON:0035805	85.27	gold quality
monocyte	CL:0000576	84.90	gold quality
secondary oocyte	CL:0000655	84.64	gold quality
body of stomach	UBERON:0001161	84.45	gold quality
mucosa of stomach	UBERON:0001199	84.39	gold quality
leukocyte	CL:0000738	84.36	gold quality
mononuclear cell	CL:0000842	84.30	gold quality
granulocyte	CL:0000094	84.25	gold quality
right lobe of liver	UBERON:0001114	84.22	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	84.14	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	83.97	gold quality
lower esophagus	UBERON:0013473	83.80	gold quality
nerve	UBERON:0001021	83.79	gold quality
tibial nerve	UBERON:0001323	83.79	gold quality
lower esophagus muscularis layer	UBERON:0035833	83.79	gold quality
ganglionic eminence	UBERON:0004023	83.43	gold quality
lower esophagus mucosa	UBERON:0035834	83.39	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.40

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
MUC1	Repression
VDR	Unknown

Upstream regulators (CollecTRI, top): SMAD2, SP1, TCF3, TP53

miRNA regulators (miRDB)

72 targeting PIAS4, 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-MIR-4673	100.00	66.64	1490
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-3613-3P	100.00	76.36	7965
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-5003-3P	99.85	69.29	2517
HSA-MIR-3663-3P	99.84	70.39	798
HSA-MIR-3680-3P	99.75	72.51	3095
HSA-MIR-6745	99.74	65.33	1321
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-5004-5P	99.68	66.63	1294
HSA-MIR-378A-5P	99.65	66.33	1311

Literature-anchored findings (GeneRIF, showing 40)

• PIASy has a role in modification of C-EBPalpha by SUMO-1 or SUMO-3 (PMID:12511558)
• PIASy suppresses GATA-2 transcriptional activity in endothelial cells. (PMID:12750312)
• PIASy has a role in regulating TGF-beta expression along with SMAD3 (PMID:12815042)
• PIASy may repress the androgen factor by recruiting histone deacetylases, independent of its SUMO ligase activity (PMID:14981544)
• IFNgamma and protein inhibitor of activated STAT-y synergistically inhibited progesterone receptor-dependent transcription (PMID:15155784)
• the inhibitory action of PIASy on BMP-regulated Smad activity was due to direct physical interactions between Smads and PIASy through its RING domain (PMID:15158472)
• PIASy is an inhibitor of TRIF-induced ISRE and NF-kappaB activation but not apoptosis (PMID:15251447)
• Sumoylation of Lys(35) in PIASy determines the nuclear localization of PIASy and it is necessary for PIASy-dependent sumoylation and transcriptional activation of Tcf-4. (PMID:15831457)
• Direct interactions between the promyelocytic leukemia (PML) body protein PIASy and the Cajal body (CB) protein coilin have a role in mediating association of CBs to PML bodies. (PMID:16219678)
• by controlling Piasy stability, Trim32 regulates UVB-induced keratinocyte apoptosis through induction of NFkappaB (PMID:16816390)
• PIASy is the first SUMO ligase for NEMO whose substrate specificity seems to be controlled by IKK interaction, subcellular targeting and oxidative stress conditions. (PMID:16906147)
• PIASgamma directs Topoisomerase II to specific chromosome regions that require efficient removal of DNA catenations prior to anaphase. The lack of this activity activates the spindle checkpoint, protecting cells from non-disjunction. (PMID:17183683)
• Results report that Yin Yang 1 protein can be sumoylated both in vivo and in vitro by PIASy, a SUMO E3 ligase. (PMID:17353273)
• PIASy controls Ets-1 function, at least in part, by inhibiting Ets-1 protein turnover via the ubiquitin-proteasome system. (PMID:17456046)
• Our results indicate that PIASy negatively regulates E1AF-mediated transcription by both E1AF sumoylation in a dependent and independent fashion. (PMID:17585876)
• PIASy has a role in down-regulation of MUC1 expression (PMID:17717071)
• provide the first evidence for the existence of a close-spatially controlled-mode of regulation of FIP200 and PIASy nucleocytoplasmic functions (PMID:18285457)
• PIASy regulates TGF-beta/Smad3-mediated signaling by stimulating sumoylation and nuclear export of Smad3. (PMID:18384750)
• As CCL20 is activated by Th17 cytokines, the upregulation of CCL20 production by Trim32 provides a positive feedback loop of CCL20 and Th17 activation in the self-perpetuating cycle of psoriasis (PMID:20054338)
• Knockdown of PIASy by small interfering RNA leads to reduction of VHL oligomerization and increases HIF1alpha degradation (PMID:20300531)
• PIASy plays an important role in regulation of p73alpha transcriptional activity and is also a regulator of the cell cycle machinery (PMID:20471636)
• Studies define an important role of PIASy in hypoxia signaling through promoting HIF1alpha SUMOylation. (PMID:20661221)
• Cav-3 is SUMOylated in a manner that is enhanced by the SUMO E3 ligase PIASy; Cav-3 SUMOylation in the mechanisms for beta(2)AR but not beta(1)AR desensitization (PMID:21362625)
• The increase of NCOA3 is essential for SYT-SSX1-mediated synovial sarcoma formation. SYT-SSX1 does so by increasing the sumoylation of NCOA3 through interaction with a SUMO E3 ligase, PIASy, as well as the sumoylation of NEMO. (PMID:21454665)
• Our study suggested that systemic sclerosis is associated with STAT gene rs7574865 polymorphism. (PMID:22173230)
• PIAS4 and the process of SUMOylation are important modulators of Vitamin D receptor-mediated signaling (PMID:22564762)
• PIASy binding to p53 and PIASy-activated Tip60 lead to K386 sumoylation and K120 acetylation of p53. (PMID:22751435)
• Protein inhibitor of activated STAT, PIASy regulates alpha-smooth muscle actin expression by interacting with E12 in mesangial cells. (PMID:22829926)
• PIASgamma fully represses Nurr1 transactivation through a direct interaction, independently of its E3-ligase activity (PMID:23358114)
• Human melanoma patient samples and cell lines maintain p53 expression but PIASy and/or Tip60 are frequently lost. (PMID:23624367)
• Evidence that PIASy is the only SUMO E3 ligase that regulates lung cancer epithelial-to-mesenchymal transition (EMT) by repressing SIRT1 transcription. (PMID:23704280)
• PIAS4 was overexpressed in pancreatic cancer cells compared with normal pancreas; it interacts with the tumour suppressor von Hippel-Lindau (VHL) and leads to VHL sumoylation, oligomerization and impaired function; study elucidates role of PIAS4 in regulation of pancreatic cancer cell growth (PMID:24002598)
• High reactive oxygen speciesinduces oxidation and ubiquitin-mediated degradation of PIASgamma, thereby disrupting PIASgamma-IKKgamma cross talk. (PMID:24457965)
• PIASgamma-dependent modification of tomosyn-1 with SUMO-2/3 presents a novel mechanism to adapt secretory strength to the dynamic synaptic environment. (PMID:24614299)
• PIAS4 (rs735842) and VEGFA (rs699947) were the most statistically significant variants associated in hypoxia pathway analysis. (PMID:25234649)
• PIAS4 was identified as a candidate gene for abnormal head size in 13 patients with proximal 19p13.3 submicroscopic rearrangements . (PMID:25853300)
• SUMOylation of RXRalpha is significantly enhanced through PIAS4-mediated activity. (PMID:26116533)
• PIAS4 activity are required for the AMPKalpha1 SUMOylation and the inhibition of AMPKalpha1 activity towards mTORC1 signalling. (PMID:26616021)
• these findings provide evidence for the effects of PIAsxalpha and its mechanism on osteosarcoma progression, which offers novel insight into sumoylation and the cell cycle in osteosarcoma. (PMID:26708148)
• Our data reveal a novel and dynamic role for PIAS4 in the cellular-mediated restriction of herpesviruses and establish a new functional role for the PIAS family of SUMO ligases in the intrinsic antiviral immune response to DNA virus infection. (PMID:26937035)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	pias4a	ENSDARG00000007081
danio_rerio	pias4b	ENSDARG00000042215
mus_musculus	Pias4	ENSMUSG00000004934
rattus_norvegicus	Pias4	ENSRNOG00000020230
drosophila_melanogaster	Su(var)2-10	FBGN0003612

Paralogs (5): PIAS1 (ENSG00000033800), PIAS2 (ENSG00000078043), ZMIZ1 (ENSG00000108175), ZMIZ2 (ENSG00000122515), PIAS3 (ENSG00000131788)

Protein

Protein identifiers

E3 SUMO-protein ligase PIAS4 — Q8N2W9 (reviewed: Q8N2W9)

Alternative names: PIASy, Protein inhibitor of activated STAT protein 4, Protein inhibitor of activated STAT protein gamma

All UniProt accessions (1): Q8N2W9

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. Mediates sumoylation of ALKBH5, AXIN1, CEBPA, KLF8, GATA2, PARK7, HERC2, MYB, TCF4 and RNF168. Plays a crucial role as a transcriptional coregulation in various cellular pathways, including the STAT pathway, the p53/TP53 pathway, the Wnt pathway and the steroid hormone signaling pathway. Involved in gene silencing. In Wnt signaling, represses LEF1 and enhances TCF4 transcriptional activities through promoting their sumoylations. Enhances the sumoylation of MTA1 and may participate in its paralog-selective sumoylation. Binds to AT-rich DNA sequences, known as matrix or scaffold attachment regions (MARs/SARs). Catalyzes conjugation of SUMO2 to KAT5 in response to DNA damage, facilitating repair of DNA double-strand breaks (DSBs) via homologous recombination (HR). Mediates sumoylation of PARP1 in response to PARP1 trapping to chromatin. Mediates sumoylation of KLF8, repressiing KLF8 transcriptional activity and cell cycle progression into G(1) phase. Sumoylates ALKBH5 downstream of MAPK8/JNK1 and MAPK9/JNK2 in response to reactive oxygen species (ROS), inhibiting ALKBH5 RNA demethylase activity.

Subunit / interactions. Interacts with AR, GATA2, LEF1, TP53 and STAT1 (IFNG-induced). Interacts with TICAM1. Interacts with MTA1. Interacts with PRDM1/Blimp-1. Interacts with TRIM32 upon treatment with UVB and TNF.

Subcellular location. Nucleus. PML body.

Tissue specificity. Highly expressed in testis and, at lower levels, in spleen, prostate, ovary, colon and peripheral blood leukocytes.

Post-translational modifications. Sumoylated. Lys-35 is the main site of sumoylation. Sumoylation is required for TCF4 sumoylation and transcriptional activation. Represses LEF1 transcriptional activity. SUMO1 is the preferred conjugate.

Domain organisation. The LXXLL motif is a coregulator signature that is essential for transcriptional corepression.

Pathway. Protein modification; protein sumoylation.

Similarity. Belongs to the PIAS family.

RefSeq proteins (1): NP_056981* (*=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: PF02037, PF02891, PF14324

UniProt features (32 total): cross-link 9, mutagenesis site 5, binding site 4, sequence conflict 3, modified residue 2, domain 2, compositionally biased region 2, initiator methionine 1, chain 1, zinc finger region 1, region of interest 1, short sequence motif 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8N2W9-F1	77.03	0.57

Functional residue map

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

Ligand- & substrate-binding residues (4): 344; 365; 368; 342

Post-translational modifications (11): 2, 114, 9, 35, 35, 56, 59, 68, 69, 125, 128

Mutagenesis-validated functional residues (5):

Position	Phenotype
23–24	loss of repression of ar- and stat1-induced transcription; no effect on ar- and stat1-binding.
35	complete loss of sumoylation. no enhancement of tcf4 sumoylation. no effect on interaction with tcf4. colocalizes with s
128	some loss of sumoylation.
342	abolished sumo ligase activity. inhibits tcf4 sumoylation. inhibits beta-catenin-mediated tcf7l2/tcf4 activity. no coloc
347	inhibits tcf4 sumoylation. inhibits beta-catenin-mediated tcf7l2/tcf4 activity. no colocalization with tcf7l2/tcf4 in nu

Function

Pathways and Gene Ontology

Reactome pathways

13 pathways

ID	Pathway
R-HSA-196791	Vitamin D (calciferol) metabolism
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-4085377	SUMOylation of SUMOylation proteins
R-HSA-4090294	SUMOylation of intracellular receptors
R-HSA-4615885	SUMOylation of DNA replication proteins
R-HSA-4755510	SUMOylation of immune response proteins
R-HSA-5693565	Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks
R-HSA-5693571	Nonhomologous End-Joining (NHEJ)
R-HSA-5693607	Processing of DNA double-strand break ends
R-HSA-69473	G2/M DNA damage checkpoint

MSigDB gene sets: 235 (showing top): GOBP_REGULATION_OF_DOUBLE_STRAND_BREAK_REPAIR, GOBP_REGULATION_OF_DNA_RECOMBINATION, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_REGULATION_OF_EPITHELIAL_CELL_APOPTOTIC_PROCESS, GOBP_REGULATION_OF_MRNA_CATABOLIC_PROCESS, GOBP_RESPONSE_TO_PEPTIDE, REACTOME_G2_M_DNA_DAMAGE_CHECKPOINT, GOBP_REGULATION_OF_PROTEIN_SUMOYLATION, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_REGULATION_OF_DOUBLE_STRAND_BREAK_REPAIR_VIA_HOMOLOGOUS_RECOMBINATION, GOBP_NEGATIVE_REGULATION_OF_TUMOR_NECROSIS_FACTOR_MEDIATED_SIGNALING_PATHWAY, GOBP_REGULATION_OF_DNA_REPAIR, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_LOCALIZATION, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION

GO Biological Process (24): negative regulation of transcription by RNA polymerase II (GO:0000122), hair follicle development (GO:0001942), double-strand break repair (GO:0006302), regulation of transcription by RNA polymerase II (GO:0006357), central nervous system development (GO:0007417), negative regulation of tumor necrosis factor-mediated signaling pathway (GO:0010804), Wnt signaling pathway (GO:0016055), protein sumoylation (GO:0016925), positive regulation of protein sumoylation (GO:0033235), vitamin D metabolic process (GO:0042359), negative regulation of canonical NF-kappaB signal transduction (GO:0043124), regulation of mRNA stability (GO:0043488), negative regulation of DNA-templated transcription (GO:0045892), limb epidermis development (GO:0060887), negative regulation of protein localization to chromatin (GO:0120186), positive regulation of keratinocyte apoptotic process (GO:1902174), positive regulation of intrinsic apoptotic signaling pathway in response to DNA damage (GO:1902231), positive regulation of double-strand break repair via homologous recombination (GO:1905168), DNA damage response (GO:0006974), regulation of gene expression (GO:0010468), negative regulation of macromolecule biosynthetic process (GO:0010558), mRNA destabilization (GO:0061157), regulation of cellular response to stress (GO:0080135), negative regulation of double-strand break repair via homologous recombination (GO:2000042)

GO Molecular Function (11): DNA binding (GO:0003677), transcription coregulator activity (GO:0003712), transcription corepressor activity (GO:0003714), zinc ion binding (GO:0008270), SUMO transferase activity (GO:0019789), ubiquitin protein ligase binding (GO:0031625), ubiquitin protein ligase activity (GO:0061630), SUMO ligase activity (GO:0061665), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (7): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), nuclear matrix (GO:0016363), PML body (GO:0016605), transferase complex (GO:1990234)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
SUMO E3 ligases SUMOylate target proteins	8
Metabolism of steroids	1
DNA Double Strand Break Response	1
DNA Double-Strand Break Repair	1
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	1
G2/M Checkpoints	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
transcription by RNA polymerase II	2
negative regulation of DNA-templated transcription	2
skin epidermis development	2
regulation of DNA-templated transcription	2
ubiquitin-like protein ligase activity	2
nuclear lumen	2
regulation of transcription by RNA polymerase II	1
hair cycle process	1
anatomical structure development	1
DNA repair	1
nervous system development	1
system development	1
negative regulation of cytokine-mediated signaling pathway	1
regulation of tumor necrosis factor-mediated signaling pathway	1
tumor necrosis factor-mediated signaling pathway	1
cell surface receptor signaling pathway	1
peptidyl-lysine modification	1
protein modification by small protein conjugation	1
protein sumoylation	1
regulation of protein sumoylation	1
positive regulation of protein modification by small protein conjugation or removal	1
steroid metabolic process	1
canonical NF-kappaB signal transduction	1
regulation of canonical NF-kappaB signal transduction	1
negative regulation of intracellular signal transduction	1
regulation of RNA stability	1
regulation of mRNA catabolic process	1
DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
limb development	1
protein localization to chromatin	1
negative regulation of protein localization	1
regulation of protein localization to chromatin	1
keratinocyte apoptotic process	1
regulation of keratinocyte apoptotic process	1
positive regulation of epithelial cell apoptotic process	1
intrinsic apoptotic signaling pathway in response to DNA damage	1
regulation of intrinsic apoptotic signaling pathway in response to DNA damage	1
positive regulation of intrinsic apoptotic signaling pathway	1

Protein interactions and networks

STRING

1796 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PIAS4	ATM	Q13315	956
PIAS4	UBE2I	P50550	928
PIAS4	SUMO2	P55855	927
PIAS4	SUMO1	P55856	885
PIAS4	RNF8	O76064	823
PIAS4	SENP1	Q9P0U3	802
PIAS4	IKBKG	Q9Y6K9	800
PIAS4	RNF168	Q8IYW5	795
PIAS4	SMAD3	P84022	792
PIAS4	RNF4	P78317	761
PIAS4	STAT1	P42224	745
PIAS4	SAE1	Q9UBE0	715
PIAS4	UBA2	Q9UBT2	686
PIAS4	CBX4	O00257	681
PIAS4	TP53BP1	Q12888	672

IntAct

229 interactions, top by confidence:

A	B	Type	Score
HTT	PIAS4	psi-mi:“MI:0915”(physical association)	0.700
PIAS4	HTT	psi-mi:“MI:0915”(physical association)	0.700
CA10	WDHD1	psi-mi:“MI:0914”(association)	0.640
TADA3	PIAS4	psi-mi:“MI:0915”(physical association)	0.630
PIAS4	ESRRA	psi-mi:“MI:0915”(physical association)	0.570
ESRRA	PIAS4	psi-mi:“MI:0915”(physical association)	0.570
ZBTB34	PIAS4	psi-mi:“MI:0915”(physical association)	0.560
PIAS4	ZBTB34	psi-mi:“MI:0915”(physical association)	0.560
TRIM38	PIAS4	psi-mi:“MI:0915”(physical association)	0.560
LCE1D	PIAS4	psi-mi:“MI:0915”(physical association)	0.560
CALR	PIAS4	psi-mi:“MI:0915”(physical association)	0.560
PIAS4	CDH1	psi-mi:“MI:0915”(physical association)	0.560
DLST	PIAS4	psi-mi:“MI:0915”(physical association)	0.560
NEFL	PIAS4	psi-mi:“MI:0915”(physical association)	0.560
TP53BP2	PIAS4	psi-mi:“MI:0915”(physical association)	0.560
CDK5R1	PIAS4	psi-mi:“MI:0915”(physical association)	0.560
PIAS4	AHCYL1	psi-mi:“MI:0915”(physical association)	0.560
PIAS4	GATA1	psi-mi:“MI:0915”(physical association)	0.560
PIAS4	HOXC4	psi-mi:“MI:0915”(physical association)	0.560
PIAS4	IFI35	psi-mi:“MI:0915”(physical association)	0.560
PIAS4	SHOX2	psi-mi:“MI:0915”(physical association)	0.560
PIAS4	SMARCD1	psi-mi:“MI:0915”(physical association)	0.560
PIAS4	BECN1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (274): PIAS4 (Affinity Capture-Western), PIAS4 (Biochemical Activity), HIC1 (Co-localization), HNF4A (Biochemical Activity), UBE2I (Reconstituted Complex), VHL (Co-localization), UBE2I (Reconstituted Complex), TOP2A (Biochemical Activity), PARP1 (Biochemical Activity), UBE2I (Reconstituted Complex), ZW10 (Reconstituted Complex), KNTC1 (Reconstituted Complex), PIAS4 (Co-localization), PIAS4 (Reconstituted Complex), PIAS4 (Reconstituted Complex)

ESM2 similar proteins: A0A974CYQ5, A5WW08, A7XUJ6, B5DF45, B6CJY4, B6CJY5, O00463, O15344, O70583, P0DW87, P0DW89, P39429, P53351, P70191, P70196, P82457, P82458, Q08CH8, Q12933, Q13114, Q28DL4, Q29RQ5, Q2TAD9, Q3KPU8, Q3MV19, Q3U9F6, Q3ZCC3, Q5FWP4, Q5R4L1, Q60803, Q61382, Q6DJN2, Q6GNX1, Q6IWL4, Q6J1I7, Q6P256, Q80WG7, Q8N2W9, Q91ZY8, Q969K3

Diamond homologs: A0A0A7EPL0, F4JYG0, O94451, Q04195, Q6P1E1, Q8CIE2, Q8N2W9, Q8NF64, Q94361, Q9JM05, Q9ULJ6, F1R4C4, O54714, O70260, O75925, O75928, O88907, Q12216, Q680Q4, Q6ASW7, Q6AZ28, Q6L4L4, Q8C5D8, Q9Y6X2, Q1MTR4

SIGNOR signaling

9 interactions.

A	Effect	B	Mechanism
PIAS4	down-regulates	SMAD3	binding
PIAS4	down-regulates	SMAD4	binding
PIAS4	down-regulates	STAT1	binding
PIAS4	up-regulates	RPA2	phosphorylation
PIAS4	up-regulates	TP53BP1	sumoylation
PIAS4	“down-regulates activity”	SMAD3/SMAD4	binding
PRKCZ	“down-regulates quantity by destabilization”	PIAS4	phosphorylation
AREL1	“down-regulates quantity by destabilization”	PIAS4	ubiquitination

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.

Reactome pathways:

Pathway	Partners	Fold	FDR
SUMOylation of transcription factors	5	45.3×	3e-05
SUMOylation of chromatin organization proteins	6	15.1×	7e-04
Apoptosis	5	13.3×	3e-03
Programmed Cell Death	5	11.6×	4e-03

GO biological processes:

GO term	Partners	Fold	FDR
protein sumoylation	5	19.5×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	68
Likely benign	14
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

2753 predictions. Top by Δscore:

Variant	Effect	Δscore
19:4007785:AAAGT:A	donor_loss	1.0000
19:4007786:AAGT:A	donor_loss	1.0000
19:4007787:AGT:A	donor_loss	1.0000
19:4007788:GTGA:G	donor_gain	1.0000
19:4007792:G:GG	donor_gain	1.0000
19:4013347:TAGG:T	donor_loss	1.0000
19:4013348:AGG:A	donor_loss	1.0000
19:4013349:GGT:G	donor_loss	1.0000
19:4013350:G:GA	donor_loss	1.0000
19:4013351:T:G	donor_loss	1.0000
19:4024034:A:AG	acceptor_gain	1.0000
19:4024035:G:GG	acceptor_gain	1.0000
19:4024035:GT:G	acceptor_gain	1.0000
19:4028125:T:TA	acceptor_gain	1.0000
19:4028508:A:AC	acceptor_loss	1.0000
19:4028508:A:AG	acceptor_gain	1.0000
19:4028509:G:GA	acceptor_gain	1.0000
19:4028509:GA:G	acceptor_gain	1.0000
19:4028509:GAAT:G	acceptor_gain	1.0000
19:4028509:GAATC:G	acceptor_gain	1.0000
19:4028601:G:GG	donor_gain	1.0000
19:4028714:TTGCA:T	acceptor_loss	1.0000
19:4028716:GCA:G	acceptor_loss	1.0000
19:4028717:CAG:C	acceptor_loss	1.0000
19:4028718:A:AG	acceptor_gain	1.0000
19:4028718:AG:A	acceptor_gain	1.0000
19:4028718:AGG:A	acceptor_gain	1.0000
19:4028719:G:GC	acceptor_loss	1.0000
19:4028719:G:GG	acceptor_gain	1.0000
19:4028719:GG:G	acceptor_gain	1.0000

AlphaMissense

3301 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:4012954:T:A	L20H	1.000
19:4012954:T:C	L20P	1.000
19:4012963:T:C	L23P	1.000
19:4012966:T:C	L24P	1.000
19:4012992:G:A	G33R	1.000
19:4012992:G:C	G33R	1.000
19:4012993:G:A	G33E	1.000
19:4012993:G:T	G33V	1.000
19:4012998:A:C	K35Q	1.000
19:4012998:A:G	K35E	1.000
19:4012999:A:T	K35M	1.000
19:4013000:G:C	K35N	1.000
19:4013000:G:T	K35N	1.000
19:4013008:T:A	L38H	1.000
19:4013008:T:C	L38P	1.000
19:4013011:T:A	V39D	1.000
19:4013017:G:T	R41M	1.000
19:4013018:G:C	R41S	1.000
19:4013018:G:T	R41S	1.000
19:4013019:G:C	A42P	1.000
19:4013020:C:A	A42D	1.000
19:4013023:T:C	L43P	1.000
19:4013029:T:C	L45P	1.000
19:4013347:T:C	L151S	1.000
19:4028178:T:A	V191D	1.000
19:4028184:T:C	L193P	1.000
19:4028187:G:C	R194T	1.000
19:4028187:G:T	R194I	1.000
19:4028510:A:C	R194S	1.000
19:4028510:A:T	R194S	1.000

dbSNP variants (sampled 300 via entrez): RS1000030136 (19:4026924 T>C), RS1000048417 (19:4037851 G>C,T), RS1000209809 (19:4030126 C>T), RS1000214899 (19:4009707 T>C,G), RS1000284377 (19:4033790 C>G,T), RS1000343848 (19:4029946 C>A), RS1000357199 (19:4018398 C>T), RS1000451413 (19:4009980 G>A,C), RS1000535049 (19:4015500 C>A,G), RS1000547277 (19:4031216 G>A), RS1000562673 (19:4014458 G>A), RS1000751000 (19:4007548 G>A,C,T), RS1000980503 (19:4011103 G>A), RS1001001487 (19:4022928 T>C), RS1001005671 (19:4038665 A>G)

Disease associations

OMIM: gene MIM:605989 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST004146_28	Chronic lymphocytic leukemia	5.000000e-08
GCST010002_146	Refractive error	2.000000e-09
GCST010242_30	HDL cholesterol levels	6.000000e-16

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004612	high density lipoprotein cholesterol measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5725174 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

21 total (human), top 21 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
TAK-243	increases sumoylation	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
11-nor-delta(9)-tetrahydrocannabinol-9-carboxylic acid	affects methylation, increases abundance	1
cobaltous chloride	increases expression	1
tanshinone II A sodium sulfonate	decreases response to substance, increases sumoylation, decreases reaction	1
testosterone-3-carboxymethyloxime-bovine serum albumin conjugate	affects expression	1
di-n-butylphosphoric acid	affects expression	1
bisphenol S	decreases methylation	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Atrazine	increases expression	1
Cannabinoids	affects methylation, increases abundance	1
Cisplatin	decreases response to substance, increases sumoylation, decreases reaction	1
Doxorubicin	decreases expression	1
Selenium	affects cotreatment, decreases expression	1
Smoke	decreases expression	1
Thiram	increases expression	1
Urethane	increases expression	1
Valproic Acid	increases methylation	1
Vitamin E	decreases expression, affects cotreatment	1
Aflatoxin B1	increases methylation	1

ChEMBL screening assays

6 unique, capped per target: 6 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5697685	Binding	Inhibition of PIAS4 (unknown origin) assessed as fold change at 10 uM incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. — Nature

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_D7X5	Ubigene A-549 PIAS4 KO	Cancer cell line	Male
CVCL_D8SJ	Ubigene HCT 116 PIAS4 KO	Cancer cell line	Male
CVCL_D9N1	Ubigene HEK293 PIAS4 KO	Transformed cell line	Female
CVCL_E0KE	Ubigene HeLa PIAS4 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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