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PIAS3

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PIAS3
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesPIAS3, ZMIZ5, protein inhibitor of activated STAT 3
External IDsOMIM: 605987; MGI: 1913126; HomoloGene: 4447; GeneCards: PIAS3; OMA:PIAS3 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

10401

229615

Ensembl

ENSG00000131788

ENSMUSG00000028101

UniProt

Q9Y6X2

O54714

RefSeq (mRNA)

NM_006099

NM_001165949
NM_018812
NM_146135

RefSeq (protein)

NP_006090

NP_001159421
NP_061282
NP_666247

Location (UCSC)Chr 1: 145.85 – 145.86 MbChr 3: 96.6 – 96.61 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

E3 SUMO-protein ligase PIAS3 is an enzyme that in humans is encoded by the PIAS3 gene.[5][6]

PIAS family

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The mammalian PIAS family consists of four members: PIAS1, PIAS2, PIAS3 and PIAS4. In Drosophila, a single PIAS homologue named dPIAS/Zimp has been identified.[7] In yeast, two PIAS-related proteins were identified namely SIZ1 and SIZ2.[8] The PIAS family contains more than 60 proteins, most of them transcription factors that can be either positively or negatively regulated through multiple mechanisms.

Discovery

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IAS proteins were originally identified in studies that were aimed to decipher the Janus Kinase (JAK)/STAT signaling pathway. Originally, PIAS3 was found to interact specifically with phosphorylated STAT3 in Interleukin -6 (IL-6) activated murine myeloblast M1 cells.[9] This interaction is mediated via PIAS3 binding to the STAT3 DNA binding domain. Hence, STAT3 transcriptional activity is inhibited by the physical prevention of its binding to target genes. Subsequently, PIAS3 was also found to be a regulator protein of other key transcription factors, including MITF,[10] NFκB,[11] SMAD[12] and estrogen receptor.[13]

Function

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PIAS3 protein also functions as a SUMO (small ubiquitin-like modifier)-E3 ligase which catalyzes the covalent attachment of a SUMO protein to specific target substrates. It directly binds to several transcription factors and either blocks or enhances their activity. Alternatively spliced transcript variants of this gene have been identified, but the full-length nature of some of these variants has not been determined.[6]

Domains

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The SAF-A/B, Acinus and PIAS (SAP) domain is located at the N-terminal of PIAS proteins.[14] This evolutionarily conserved domain is found in proteins ranging from yeast to human and is shared by other chromatin-binding proteins, such as scaffold attachment factor A and B.[15] The SAP domain can recognize and bind to AT-rich DNA sequences present in scaffold-attachment regions/matrix-attachment regions.[16] These elements are frequently found near gene enhancers and interact with nuclear matrix proteins to provide a unique nuclear microenvironment for transcriptional regulation. An LXXLL signature motif is present within the SAP domain of all PIAS proteins. This signature motif has been shown to mediate interactions between nuclear receptors and their co-regulators.[17] It is also essential for the binding of PIAS3 to androgen receptor. The LXXLL motif represents the minimal requirement for the interaction with the NFκB p65 subunit and for the inhibition of NFκB transcriptional activity.[11] It was previously described that the LXXLL motif is also responsible for the retention of PIAS3 in the nucleus.

The Pro-Ile-Asn-Ile-Thr (PINIT) motif represents a highly conserved region of PIAS proteins, which was shown to be involved in the nuclear retention of PIAS3.[18] Within the PINIT domain, the PIAS382-132 region was isolated and characterized as an inhibitory domain that binds and inhibits both the MITF and STAT3 transcription factors.[19] The RING-finger-like zinc-binding domain (RLD) is one of the most conserved domains of the PIAS family and has been shown to be important for PIAS3 activity as a SUMO-E3 ligase.[20] The RLD domain is also involved in the positive regulation of SMAD3 by PIAS3.[21]

Interactions

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PIAS3 has been shown to interact with:

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References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000131788 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000028101 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Ueki N, Seki N, Yano K, Saito T, Masuho Y, Muramatsu M (June 1999). "Isolation and chromosomal assignment of a human gene encoding protein inhibitor of activated STAT3 (PIAS3)". Journal of Human Genetics. 44 (3): 193–6. doi:10.1007/s100380050141. PMID 10319586. S2CID 12454718.
  6. ^ a b "Entrez Gene: PIAS3 protein inhibitor of activated STAT, 3".
  7. ^ Mohr SE, Boswell RE (Mar 1999). "Zimp encodes a homologue of mouse Miz1 and PIAS3 and is an essential gene in Drosophila melanogaster". Gene. 229 (1–2): 109–16. doi:10.1016/s0378-1119(99)00033-5. PMID 10095110.
  8. ^ Islam HK, Fujioka Y, Tomidokoro T, Sugiura H, Takahashi T, Kondo S, Katoh H (2001). "Immunohistochemical study of genetic alterations in intraductal and invasive ductal tumors of the pancreas". Hepato-Gastroenterology. 48 (39): 879–83. PMID 11462947.
  9. ^ Chung CD, Liao J, Liu B, Rao X, Jay P, Berta P, Shuai K (Dec 1997). "Specific inhibition of Stat3 signal transduction by PIAS3". Science. 278 (5344): 1803–5. Bibcode:1997Sci...278.1803C. doi:10.1126/science.278.5344.1803. PMID 9388184.
  10. ^ a b Levy C, Nechushtan H, Razin E (Jan 2002). "A new role for the STAT3 inhibitor, PIAS3: a repressor of microphthalmia transcription factor". The Journal of Biological Chemistry. 277 (3): 1962–6. doi:10.1074/jbc.m109236200. PMID 11709556. S2CID 25141003.
  11. ^ a b c Jang HD, Yoon K, Shin YJ, Kim J, Lee SY (Jun 2004). "PIAS3 suppresses NF-kappaB-mediated transcription by interacting with the p65/RelA subunit". The Journal of Biological Chemistry. 279 (23): 24873–80. doi:10.1074/jbc.m313018200. PMID 15140884. S2CID 20036187.
  12. ^ Bava KA, Gromiha MM, Uedaira H, Kitajima K, Sarai A (2004). "ProTherm, version 4.0: thermodynamic database for proteins and mutants". Nucleic Acids Research. 32 (Database issue): D120–1. doi:10.1093/nar/gkh082. PMC 308816. PMID 14681373.
  13. ^ Sentis S, Le Romancer M, Bianchin C, Rostan MC, Corbo L (2005). "Sumoylation of the estrogen receptor alpha hinge region regulates its transcriptional activity". Molecular Endocrinology. 19 (11): 2671–84. doi:10.1210/me.2005-0042. PMID 15961505.
  14. ^ Shuai K (Feb 2006). "Regulation of cytokine signaling pathways by PIAS proteins". Cell Research. 16 (2): 196–202. doi:10.1038/sj.cr.7310027. PMID 16474434. S2CID 755228.
  15. ^ Aravind L, Koonin EV (2000). "SAP - a putative DNA-binding motif involved in chromosomal organization". Trends in Biochemical Sciences. 25 (3): 112–4. doi:10.1016/s0968-0004(99)01537-6. PMID 10694879.
  16. ^ Kipp, M.; et al. (2000). "SAF-Box, a conserved protein domain that specifically recognizes scaffold attachment region DNA". Mol Cell Biol. 20 (20): 7480–7489. doi:10.1128/mcb.20.20.7480-7489.2000. PMC 86301. PMID 11003645.
  17. ^ Glass CK, Rosenfeld MG (Jan 2000). "The coregulator exchange in transcriptional functions of nuclear receptors". Genes & Development. 14 (2): 121–41. doi:10.1101/gad.14.2.121. PMID 10652267. S2CID 12793980.
  18. ^ Duval D, Duval G, Kedinger C, Poch O, Boeuf H (Nov 2003). "The 'PINIT' motif, of a newly identified conserved domain of the PIAS protein family, is essential for nuclear retention of PIAS3L". FEBS Letters. 554 (1–2): 111–8. doi:10.1016/s0014-5793(03)01116-5. PMID 14596924. S2CID 23261716.
  19. ^ Levy C, Khaled M, Fisher DE (Sep 2006). "MITF: master regulator of melanocyte development and melanoma oncogene". Trends in Molecular Medicine. 12 (9): 406–14. doi:10.1016/j.molmed.2006.07.008. PMID 16899407.
  20. ^ Nakagawa, K.; Yokosawa, H. (2002). "PIAS3 induces SUMO-1 modification and transcriptional repression of IRF-1". FEBS Lett. 530 (1–3): 204–208. doi:10.1016/s0014-5793(02)03486-5. PMID 12387893. S2CID 38456991.
  21. ^ Long J, Wang G, Matsuura I, He D, Liu F (Jan 2004). "Activation of Smad transcriptional activity by protein inhibitor of activated STAT3 (PIAS3)". Proceedings of the National Academy of Sciences of the United States of America. 101 (1): 99–104. Bibcode:2004PNAS..101...99L. doi:10.1073/pnas.0307598100. PMC 314145. PMID 14691252.
  22. ^ Rödel B, Tavassoli K, Karsunky H, Schmidt T, Bachmann M, Schaper F, Heinrich P, Shuai K, Elsässer HP, Möröy T (Nov 2000). "The zinc finger protein Gfi-1 can enhance STAT3 signaling by interacting with the STAT3 inhibitor PIAS3". EMBO J. 19 (21): 5845–55. doi:10.1093/emboj/19.21.5845. PMC 305799. PMID 11060035.
  23. ^ Zentner MD, Lin HH, Deng HT, Kim KJ, Shih HM, Ann DK (Aug 2001). "Requirement for high mobility group protein HMGI-C interaction with STAT3 inhibitor PIAS3 in repression of alpha-subunit of epithelial Na+ channel (alpha-ENaC) transcription by Ras activation in salivary epithelial cells". J. Biol. Chem. 276 (32): 29805–14. doi:10.1074/jbc.M103153200. PMID 11390395. S2CID 33084417.
  24. ^ Yagil Z, Nechushtan H, Kay G, Yang CM, Kemeny DM, Razin E (May 2010). "The enigma of the role of protein inhibitor of activated STAT3 (PIAS3) in the immune response". Trends Immunol. 31 (5): 199–204. doi:10.1016/j.it.2010.01.005. PMID 20181527.
  25. ^ a b Long J, Wang G, Matsuura I, He D, Liu F (Jan 2004). "Activation of Smad transcriptional activity by protein inhibitor of activated STAT3 (PIAS3)". Proc. Natl. Acad. Sci. U.S.A. 101 (1): 99–104. Bibcode:2004PNAS..101...99L. doi:10.1073/pnas.0307598100. PMC 314145. PMID 14691252.
  26. ^ Klopocki E, Schulze H, Strauss G, Ott CE, Hall J, Trotier F, Fleischhauer S, Greenhalgh L, Newbury-Ecob RA, Neumann LM, Habenicht R, König R, Seemanova E, Megarbane A, Ropers HH, Ullmann R, Horn D, Mundlos S (Feb 2007). "Complex inheritance pattern resembling autosomal recessive inheritance involving a microdeletion in thrombocytopenia-absent radius syndrome". American Journal of Human Genetics. 80 (2): 232–40. doi:10.1086/510919. PMC 1785342. PMID 17236129.

Further reading

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  • Overview of all the structural information available in the PDB for UniProt: Q9Y6X2 (E3 SUMO-protein ligase PIAS3) at the PDBe-KB.
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