PIAS4_MOUSE
ID PIAS4_MOUSE Reviewed; 507 AA.
AC Q9JM05; Q8R165;
DT 19-SEP-2003, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-2003, sequence version 2.
DT 03-AUG-2022, entry version 182.
DE RecName: Full=E3 SUMO-protein ligase PIAS4;
DE EC=2.3.2.27;
DE AltName: Full=PIASy {ECO:0000303|PubMed:11731474};
DE AltName: Full=Protein inhibitor of activated STAT protein 4;
DE AltName: Full=Protein inhibitor of activated STAT protein gamma;
DE Short=PIAS-gamma;
GN Name=Pias4; Synonyms=Piasg;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090 {ECO:0000312|EMBL:AAF72040.1};
RN [1] {ECO:0000305}
RP NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY, AND DEVELOPMENTAL STAGE.
RC TISSUE=Brain;
RX PubMed=10854042; DOI=10.1385/jmn:14:1-2:107;
RA Sturm S., Koch M., White F.A.;
RT "Cloning and analysis of a murine Pias family member, Pias-gamma, in
RT developing skin and neurons.";
RL J. Mol. Neurosci. 14:107-121(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Kidney;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [3] {ECO:0000305}
RP FUNCTION, INTERACTION WITH LEF1, DNA-BINDING, SUMOYLATION, SUBCELLULAR
RP LOCATION, AND MUTAGENESIS OF CYS-330; CYS-335; HIS-337; CYS-340 AND
RP 470-SER--SER-474.
RX PubMed=11731474; DOI=10.1101/gad.944801;
RA Sachdev S., Bruhn L., Sieber H., Pichler A., Melchior F., Grosschedl R.;
RT "PIASy, a nuclear matrix-associated SUMO E3 ligase, represses LEF1 activity
RT by sequestration into nuclear bodies.";
RL Genes Dev. 15:3088-3103(2001).
RN [4]
RP TISSUE SPECIFICITY.
RX PubMed=12750312; DOI=10.1161/01.res.0000076893.70898.36;
RA Chun T.-H., Itoh H., Subramanian L., Iniguez-Lluhi J.A., Nakao K.;
RT "Modification of GATA-2 transcriptional activity in endothelial cells by
RT the SUMO E3 ligase PIASy.";
RL Circ. Res. 92:1201-1208(2003).
RN [5]
RP SUBCELLULAR LOCATION, INTERACTION WITH TRIM32, AND UBIQUITINATION.
RX PubMed=16816390; DOI=10.1074/jbc.m601655200;
RA Albor A., El-Hizawi S., Horn E.J., Laederich M., Frosk P., Wrogemann K.,
RA Kulesz-Martin M.;
RT "The interaction of Piasy with Trim32, an E3-ubiquitin ligase mutated in
RT limb-girdle muscular dystrophy type 2H, promotes Piasy degradation and
RT regulates UVB-induced keratinocyte apoptosis through NFkappaB.";
RL J. Biol. Chem. 281:25850-25866(2006).
RN [6]
RP INTERACTION WITH MOMLV CA.
RX PubMed=16352559; DOI=10.1128/jvi.80.1.342-352.2006;
RA Yueh A., Leung J., Bhattacharyya S., Perrone L.A., de los Santos K.,
RA Pu S.-Y., Goff S.P.;
RT "Interaction of moloney murine leukemia virus capsid with Ubc9 and PIASy
RT mediates SUMO-1 addition required early in infection.";
RL J. Virol. 80:342-352(2006).
RN [7]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Testis;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
CC -!- FUNCTION: Functions as an E3-type small ubiquitin-like modifier (SUMO)
CC ligase, stabilizing the interaction between UBE2I and the substrate,
CC and as a SUMO-tethering factor. Mediates sumoylation of CEBPA, PARK7,
CC HERC2, MYB, TCF4 and RNF168. Plays a crucial role as a transcriptional
CC coregulation in various cellular pathways, including the STAT pathway,
CC the p53/TP53 pathway, the Wnt pathway and the steroid hormone signaling
CC pathway. Involved in gene silencing. In Wnt signaling, represses LEF1
CC and enhances TCF4 transcriptional activities through promoting their
CC sumoylations. Enhances the sumoylation of MTA1 and may participate in
CC its paralog-selective sumoylation (By similarity). Binds to AT-rich DNA
CC sequences, known as matrix or scaffold attachment regions (MARs/SARs)
CC (PubMed:11731474). Catalyzes conjugation of SUMO2 to KAT5 in response
CC to DNA damage, facilitating repair of DNA double-strand breaks (DSBs)
CC via homologous recombination (HR) (By similarity).
CC {ECO:0000250|UniProtKB:Q8N2W9, ECO:0000269|PubMed:11731474}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine +
CC [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-
CC cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine.;
CC EC=2.3.2.27; Evidence={ECO:0000250|UniProtKB:Q8N2W9};
CC -!- PATHWAY: Protein modification; protein sumoylation.
CC {ECO:0000250|UniProtKB:Q8N2W9}.
CC -!- SUBUNIT: Interacts with AR, AXIN1, GATA2, TP53 and STAT1 (IFNG-induced)
CC (By similarity). Interacts with LEF1 (PubMed:11731474). Interacts with
CC TICAM1 (By similarity). Interacts with KLF8; the interaction results in
CC SUMO ligation and repression of KLF8 transcriptional activity and of
CC its cell cycle progression into G(1) phase (By similarity). Interacts
CC with MTA1 (By similarity). Interacts with PRDM1/Blimp-1 (By
CC similarity). Interacts with TRIM32 upon treatment with UVB and TNF-
CC alpha (PubMed:16816390). {ECO:0000250|UniProtKB:Q8N2W9,
CC ECO:0000269|PubMed:11731474, ECO:0000269|PubMed:16816390}.
CC -!- SUBUNIT: (Microbial infection) Interacts ewith Moloney murine leukemia
CC virus Capsid protein p30. {ECO:0000269|PubMed:16352559}.
CC -!- SUBCELLULAR LOCATION: Nucleus, PML body {ECO:0000269|PubMed:11731474,
CC ECO:0000269|PubMed:16816390}. Note=Colocalizes with SUMO1 and
CC TCF7L2/TCF4 and LEF1 in a subset of PML (promyelocytic leukemia)
CC nuclear bodies. Accumulates in the cytoplasm upon treatment with UVB
CC and TNF-alpha. {ECO:0000250|UniProtKB:Q8N2W9}.
CC -!- TISSUE SPECIFICITY: Widely expressed, with highest levels in testis.
CC Also expressed in vascular endothelial cells, in primary keratinocytes
CC and in the CNS, including cortex, olfactory bulb, spinal cord, thalamus
CC and trigeminal ganglion. Low expression, if any, in liver and lung.
CC {ECO:0000269|PubMed:10854042, ECO:0000269|PubMed:12750312}.
CC -!- DEVELOPMENTAL STAGE: At 8.5 dpc, expressed primarily in the anterior
CC part of the neural tube. At 10.5 dpc, expressed in the neuroepithelium
CC of the forebrain and hindbrain. At 11.5 dpc, detected in the neural
CC tube, eye, limb buds and brachial arches. At 12.5 dpc, expressed in the
CC hindlimbs and forelimbs, as well as in the forebrain. At 12.5 and 13.5
CC dpc, detected in single cells in the marginal zone of the developing
CC cortex, as well as in other developing tissues and organs. At 13.5 dpc,
CC expressed in the developing limb buds, in single cells in the
CC mesenchyme surrounding future digit structures. At 15.5 dpc, detected
CC in the inner root sheath of vibrissa hair follicle. Expression in the
CC inner root sheath of the hair follicle continues later in life as it
CC can also be detected in the back skin of newborn at postnatal day 3. At
CC 16.5 dpc, expressed in the epithelium of olfactory and in the retina.
CC {ECO:0000269|PubMed:10854042}.
CC -!- DOMAIN: The LXXLL motif is a coregulator signature that is essential
CC for transcriptional corepression. {ECO:0000250|UniProtKB:Q8N2W9}.
CC -!- PTM: Sumoylated. Lys-35 is the main site of sumoylation. Sumoylation is
CC required for TCF4 sumoylation and transcriptional activation. Represses
CC LEF1 transcriptional activity. SUMO1 is the preferred conjugate.
CC {ECO:0000269|PubMed:11731474}.
CC -!- PTM: Ubiquitinated by TRIM32 upon treatment with UVB and TNF-alpha.
CC {ECO:0000269|PubMed:16816390}.
CC -!- SIMILARITY: Belongs to the PIAS family. {ECO:0000305}.
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DR EMBL; AF109174; AAF72040.1; -; mRNA.
DR EMBL; BC025159; AAH25159.1; -; mRNA.
DR CCDS; CCDS35992.1; -.
DR RefSeq; NP_067476.2; NM_021501.4.
DR AlphaFoldDB; Q9JM05; -.
DR SMR; Q9JM05; -.
DR BioGRID; 208475; 6.
DR DIP; DIP-60971N; -.
DR IntAct; Q9JM05; 2.
DR STRING; 10090.ENSMUSP00000005064; -.
DR iPTMnet; Q9JM05; -.
DR PhosphoSitePlus; Q9JM05; -.
DR EPD; Q9JM05; -.
DR MaxQB; Q9JM05; -.
DR PaxDb; Q9JM05; -.
DR PRIDE; Q9JM05; -.
DR ProteomicsDB; 287717; -.
DR Antibodypedia; 1762; 365 antibodies from 37 providers.
DR DNASU; 59004; -.
DR Ensembl; ENSMUST00000005064; ENSMUSP00000005064; ENSMUSG00000004934.
DR GeneID; 59004; -.
DR KEGG; mmu:59004; -.
DR UCSC; uc007ggc.3; mouse.
DR CTD; 51588; -.
DR MGI; MGI:2136940; Pias4.
DR VEuPathDB; HostDB:ENSMUSG00000004934; -.
DR eggNOG; KOG2169; Eukaryota.
DR GeneTree; ENSGT01030000234539; -.
DR InParanoid; Q9JM05; -.
DR OMA; YETRYNK; -.
DR OrthoDB; 1205949at2759; -.
DR PhylomeDB; Q9JM05; -.
DR TreeFam; TF323787; -.
DR Reactome; R-MMU-196791; Vitamin D (calciferol) metabolism.
DR Reactome; R-MMU-3108214; SUMOylation of DNA damage response and repair proteins.
DR Reactome; R-MMU-3232118; SUMOylation of transcription factors.
DR Reactome; R-MMU-3232142; SUMOylation of ubiquitinylation proteins.
DR Reactome; R-MMU-3899300; SUMOylation of transcription cofactors.
DR Reactome; R-MMU-4085377; SUMOylation of SUMOylation proteins.
DR Reactome; R-MMU-4090294; SUMOylation of intracellular receptors.
DR Reactome; R-MMU-4615885; SUMOylation of DNA replication proteins.
DR Reactome; R-MMU-4755510; SUMOylation of immune response proteins.
DR Reactome; R-MMU-5693565; Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks.
DR Reactome; R-MMU-5693571; Nonhomologous End-Joining (NHEJ).
DR Reactome; R-MMU-5693607; Processing of DNA double-strand break ends.
DR Reactome; R-MMU-69473; G2/M DNA damage checkpoint.
DR UniPathway; UPA00886; -.
DR BioGRID-ORCS; 59004; 5 hits in 73 CRISPR screens.
DR ChiTaRS; Pias4; mouse.
DR PRO; PR:Q9JM05; -.
DR Proteomes; UP000000589; Chromosome 10.
DR RNAct; Q9JM05; protein.
DR Bgee; ENSMUSG00000004934; Expressed in seminiferous tubule of testis and 256 other tissues.
DR ExpressionAtlas; Q9JM05; baseline and differential.
DR Genevisible; Q9JM05; MM.
DR GO; GO:0005737; C:cytoplasm; ISO:MGI.
DR GO; GO:0016363; C:nuclear matrix; IDA:MGI.
DR GO; GO:0005654; C:nucleoplasm; IDA:MGI.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0016605; C:PML body; IEA:UniProtKB-SubCell.
DR GO; GO:1990234; C:transferase complex; IDA:BHF-UCL.
DR GO; GO:0003677; F:DNA binding; IDA:MGI.
DR GO; GO:0008022; F:protein C-terminus binding; ISO:MGI.
DR GO; GO:0061665; F:SUMO ligase activity; IDA:BHF-UCL.
DR GO; GO:0019789; F:SUMO transferase activity; IDA:MGI.
DR GO; GO:0003712; F:transcription coregulator activity; IBA:GO_Central.
DR GO; GO:0003714; F:transcription corepressor activity; IDA:MGI.
DR GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:BHF-UCL.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR GO; GO:0007417; P:central nervous system development; IEP:UniProtKB.
DR GO; GO:0001942; P:hair follicle development; IEP:UniProtKB.
DR GO; GO:0060887; P:limb epidermis development; IEP:UniProtKB.
DR GO; GO:0032088; P:negative regulation of NF-kappaB transcription factor activity; IDA:BHF-UCL.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IDA:BHF-UCL.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; ISS:UniProtKB.
DR GO; GO:0010804; P:negative regulation of tumor necrosis factor-mediated signaling pathway; IMP:MGI.
DR GO; GO:1905168; P:positive regulation of double-strand break repair via homologous recombination; ISS:UniProtKB.
DR GO; GO:1902231; P:positive regulation of intrinsic apoptotic signaling pathway in response to DNA damage; IDA:MGI.
DR GO; GO:1902174; P:positive regulation of keratinocyte apoptotic process; IDA:BHF-UCL.
DR GO; GO:0033235; P:positive regulation of protein sumoylation; ISS:UniProtKB.
DR GO; GO:0016925; P:protein sumoylation; IDA:BHF-UCL.
DR GO; GO:0007259; P:receptor signaling pathway via JAK-STAT; ISA:MGI.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR GO; GO:0016055; P:Wnt signaling pathway; IEA:UniProtKB-KW.
DR Gene3D; 1.10.720.30; -; 1.
DR Gene3D; 2.60.120.780; -; 1.
DR Gene3D; 3.30.40.10; -; 1.
DR InterPro; IPR027224; PIAS4.
DR InterPro; IPR023321; PINIT.
DR InterPro; IPR038654; PINIT_sf.
DR InterPro; IPR003034; SAP_dom.
DR InterPro; IPR036361; SAP_dom_sf.
DR InterPro; IPR004181; Znf_MIZ.
DR InterPro; IPR013083; Znf_RING/FYVE/PHD.
DR PANTHER; PTHR10782:SF9; PTHR10782:SF9; 1.
DR Pfam; PF14324; PINIT; 1.
DR Pfam; PF02891; zf-MIZ; 1.
DR SMART; SM00513; SAP; 1.
DR SUPFAM; SSF68906; SSF68906; 1.
DR PROSITE; PS51466; PINIT; 1.
DR PROSITE; PS50800; SAP; 1.
DR PROSITE; PS51044; ZF_SP_RING; 1.
PE 1: Evidence at protein level;
KW Acetylation; DNA-binding; Host-virus interaction; Isopeptide bond;
KW Metal-binding; Nucleus; Reference proteome; Repressor; Transcription;
KW Transcription regulation; Transferase; Ubl conjugation;
KW Ubl conjugation pathway; Wnt signaling pathway; Zinc; Zinc-finger.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000250|UniProtKB:Q8N2W9"
FT CHAIN 2..507
FT /note="E3 SUMO-protein ligase PIAS4"
FT /id="PRO_0000218983"
FT DOMAIN 12..46
FT /note="SAP"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00186,
FT ECO:0000305"
FT DOMAIN 112..272
FT /note="PINIT"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00799"
FT ZN_FING 304..385
FT /note="SP-RING-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00452"
FT REGION 426..507
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 20..24
FT /note="LXXLL motif"
FT COMPBIAS 471..488
FT /note="Acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 335
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00452"
FT BINDING 337
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00452"
FT BINDING 358
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00452"
FT BINDING 361
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00452"
FT MOD_RES 2
FT /note="N-acetylalanine"
FT /evidence="ECO:0000250|UniProtKB:Q8N2W9"
FT MOD_RES 107
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q8N2W9"
FT CROSSLNK 9
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0000250|UniProtKB:Q8N2W9"
FT CROSSLNK 35
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO); alternate"
FT /evidence="ECO:0000250|UniProtKB:Q8N2W9"
FT CROSSLNK 35
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2); alternate"
FT /evidence="ECO:0000250|UniProtKB:Q8N2W9"
FT CROSSLNK 56
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0000250|UniProtKB:Q8N2W9"
FT CROSSLNK 59
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0000250|UniProtKB:Q8N2W9"
FT CROSSLNK 68
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0000250|UniProtKB:Q8N2W9"
FT CROSSLNK 69
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0000250|UniProtKB:Q8N2W9"
FT CROSSLNK 118
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0000250|UniProtKB:Q8N2W9"
FT CROSSLNK 128
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO)"
FT /evidence="ECO:0000250|UniProtKB:Q8N2W9"
FT MUTAGEN 330
FT /note="C->S: Abrogates sumoylation of LEF1 and increases
FT LEF1-mediated transcriptional activity; when associated
FT with S-335; A-337 and S-340."
FT /evidence="ECO:0000269|PubMed:11731474"
FT MUTAGEN 335
FT /note="C->S: Abrogates sumoylation of LEF1 and increases
FT LEF1-mediated transcriptional activity; when associated
FT with S-330; A-337 and S-340."
FT /evidence="ECO:0000269|PubMed:11731474"
FT MUTAGEN 337
FT /note="H->A: Abrogates sumoylation of LEF1 and increases
FT LEF1-mediated transcriptional activity; when associated
FT with S-330; S-335 and S-340."
FT /evidence="ECO:0000269|PubMed:11731474"
FT MUTAGEN 340
FT /note="C->S: Abrogates sumoylation of LEF1 and increases
FT LEF1-mediated transcriptional activity; when associated
FT with S-330; S-335 and A-337."
FT /evidence="ECO:0000269|PubMed:11731474"
FT MUTAGEN 470..474
FT /note="SSSSS->AAAAA: No effect on sumoylation of LEF1, nor
FT on LEF1-binding."
FT /evidence="ECO:0000269|PubMed:11731474"
FT CONFLICT 230
FT /note="K -> N (in Ref. 1; AAF72040)"
FT /evidence="ECO:0000305"
FT CONFLICT 417
FT /note="L -> H (in Ref. 1; AAF72040)"
FT /evidence="ECO:0000305"
FT CONFLICT 494
FT /note="K -> N (in Ref. 1; AAF72040)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 507 AA; 55570 MW; A8E5E6E3BAC76426 CRC64;
MAAELVEAKN MVMSFRVSDL QMLLGFVGRS KSGLKHELVT RALQLVQFDC SPELFKKIKE
LYETRYAKKS AEPGPQAPRP LDPLALHSMP RTPLSGPTVD YPVLYGKYLN GLGRLPTKTL
KPEVRLVKLP FFNMLDELLK PTELVPQSAE KLQESPCIFA LTPRQVEMIR NSRELQPGVK
AVQVVLRICY SDTSCPQEDQ YPPNIAVKVN HSYCSVPGYY PSNKPGVEPK RPCRPINLTH
LMYLSSATNR ITVTWGNYGK SYSVALYLVR QLTSSDLLQR LKTIGVKHPE LCKALVKEKL
RLDPDSEIAT TGVRVSLICP LVKMRLSVPC RAETCAHLQC FDAVFYLQMN EKKPTWMCPV
CDKPAAYDQL IIDGLLSKIL SECEGADEIE FLAEGSWRPI RAEKEPSCSP QGPILVLGTS
DANGLAPASS TPGIGSGLSG PGSAGSGAGA AGSLENGKTG ADVVDLTLDS SSSSEDEDED
EDDDEDEDEG PRPKRRCPFQ KGLVPAC
