Alternative titles; symbols
HGNC Approved Gene Symbol: PIAS1
Cytogenetic location: 15q23 Genomic coordinates (GRCh38): 15:68,054,315-68,193,847 (from NCBI)
STAT proteins are latent cytoplasmic transcription factors that become activated by tyrosine phosphorylation in response to cytokine stimulation. Using a yeast 2-hybrid screen with a portion of STAT1 (600555) as bait, Liu et al. (1998) isolated a B-cell cDNA encoding a protein that they designated PIAS1. By searching an EST database and by library screening, they identified cDNAs encoding several other members of the mammalian PIAS family including human PIASX-alpha (603567) and mouse Pias1. Like other members of the PIAS family, the predicted 650-amino acid human PIAS1 protein contains a putative zinc-binding motif and a highly acidic region.
Independently, Valdez et al. (1997) identified PIAS1 as GBP (Gu-binding protein), a protein that bound to the Gu autoantigen/RNA helicase II in yeast 2-hybrid studies. Using immunofluorescence, they found that epitope-tagged GBP localized to the nucleus in a speckled or in a diffuse pattern. Northern blot analysis detected highest expression of the 2.2-kb GBP mRNA in testis. Liu et al. (1998) noted that the reported GBP sequence lacks 9 amino acids at the N terminus and differs in several positions compared to the sequence of PIAS1.
Liu et al. (1998) found that PIAS1 inhibited STAT1-mediated gene activation in response to interferon when expressed in mammalian cells. Coimmunoprecipitation studies suggested that PIAS1 associated specifically with STAT1 in vivo upon cytokine stimulation. PIAS1, but not other PIAS proteins, inhibited the DNA binding activity of STAT1 in vitro. Liu et al. (1998) suggested that PIAS1 is a specific inhibitor of STAT1-mediated gene activation and that PIAS proteins block STAT-mediated gene activation through the inhibition of STAT-DNA binding activity.
Kahyo et al. (2001) isolated PIAS1 as a SUMO1 (601912)-binding protein by yeast 2-hybrid screening. In addition, PIAS1 bound p53 (191170) and UBC9 (601661). PIAS1 that was mutated in the RING finger-like domain bound p53 and SUMO1, but not UBC9. PIAS1 catalyzed the sumoylation of p53 both in U2OS cells and in vitro in a domain-dependent manner. These data suggested that PIAS1 functions as a SUMO ligase, or possibly as a tightly bound regulator of it, toward p53.
By a yeast 2-hybrid screen and coimmunoprecipitation experiments, Weiskirchen et al. (2001) demonstrated specific binding between PIAS1 and the C-terminal LIM domain of CSRP2 (601871).
In mouse cells, Lee et al. (2006) found that interaction of Msx1 (142983) with Pias1 was required for Msx1 to function as an inhibitor of myoblast differentiation through repression of myogenic regulatory genes, such as Myod (159970). Msx1 sumoylation was not required for its inhibitory function or its interaction with Pias1. Pias1 was required for the localization and retention of Msx1 at the nuclear periphery in mouse myoblast cells, where it colocalized with Msx1-repressed myogenic regulatory genes.
cAMP is required for the progesterone-induced differentiation of human endometrial stromal cells (HESCs) into decidual cells. Jones et al. (2006) showed that cAMP signaling attenuated ligand-dependent sumoylation of progesterone receptor (PGR; 607311) in HESCs. They found that PIAS1 interacted with PGR and served as its E3 SUMO ligase upon receptor activation. Silencing PIAS1 not only enhanced PGR-dependent transcription, but also induced expression of prolactin (PRL; 176760), a decidual marker gene, in progestin-treated HESCs without the need of simultaneous activation of the cAMP pathway. Jones et al. (2006) concluded that dynamic changes in the SUMO pathway mediated by cAMP signaling determine the endometrial response to progesterone.
Liu et al. (2007) found that PIAS1 was rapidly phosphorylated at ser90 in response to inflammatory stimuli. Mutational analysis indicated that ser90 phosphorylation was required for PIAS1 to repress transcription. In response to TNF (191160), wildtype PIAS1, but not PIAS1 with a ser90-to-ala mutation, rapidly associated with promoters of NFKB (see 164011) target genes. IKKA (CHUK; 600664), but not IKKB (IKBKB; 603258), interacted with PIAS1 in vivo and mediated PIAS1 ser90 phosphorylation, which in turn required the SUMO ligase activity of PIAS1. Liu et al. (2007) concluded that proinflammatory stimuli activate IKKA-mediated sumoylation-dependent phosphorylation of PIAS1, and that this pathway can repress inflammatory gene activation.
Galanty et al. (2009) demonstrated that SUMO1, SUMO2 (603042), and SUMO3 (602231) accumulate at double-strand DNA break sites in mammalian cells, with SUMO1 and SUMO2/3 accrual requiring the E3 ligase enzymes PIAS4 (605989) and PIAS1. Galanty et al. (2009) also established that PIAS1 and PIAS4 are recruited to damage sites via mechanisms requiring their SAP domains, and are needed for the productive association of 53BP1 (605230), BRCA1 (113705), and RNF168 (612688) with such regions. Furthermore, Galanty et al. (2009) showed that PIAS1 and PIAS4 promote double-strand break repair and confer ionizing radiation resistance. Finally, the authors established that PIAS1 and PIAS4 are required for effective ubiquitin adduct formation mediated by RNF8, RNF168, and BRCA1 at sites of DNA damage. Galanty et al. (2009) concluded that their findings identified PIAS1 and PIAS4 as components of the DNA damage response and revealed how protein recruitment to DNA double-strand break sites is controlled by coordinated sumoylation and ubiquitylation.
Liu et al. (2010) reported that the SUMO E3 ligase PIAS1 restricts the differentiation of natural T regulatory cells by maintaining a repressive chromatin state of the FOXP3 (300292) promoter. PIAS1 acts by binding to the FOXP3 promoter to recruit DNA methyltransferases and heterochromatin protein-1 (CBX5; 604478) for epigenetic modifications. PIAS1 deletion caused promoter demethylation, reduced histone H3 (see 602810) methylation at lys9, and enhanced promoter accessibility. Consistently, Pias1-null mice displayed an increased natural T regulatory cell population and were resistant to the development of experimental autoimmune encephalomyelitis. Liu et al. (2010) concluded that their studies identified an epigenetic mechanism that negatively regulates the differentiation of natural T regulatory cells.
Weiskirchen et al. (2001) mapped the PIAS1 gene to chromosome 15q22 by fluorescence in situ hybridization.
Using homologous recombination, Liu et al. (2004) generated mice lacking Pias1. These mice were fertile, but appeared to suffer elevated perinatal mortality and were runted compared with wildtype mice. Pias1 -/- bone marrow cells treated with gamma-interferon (IFNG; 147570) expressed higher levels of Gbp1 (600411), Cxcl9 (601704), and Cxcl10 (147310) than wildtype cells. Chromatin immunoprecipitation assays showed that binding of Stat1 to the Gbp1 promoter was increased in Pias1 -/- macrophages. Immunoblot, plaque assay, and PCR analyses demonstrated enhanced Ifn-mediated antiviral activity in Pias1 -/- cells. Pias1 -/- mice were more sensitive than wildtype mice to endotoxin shock. Liu et al. (2004) concluded that PIAS1 is critical for IFNG- or IFNB (147640)-mediated innate immune responses and is a physiologically important negative regulator of STAT1.
Galanty, Y., Belotserkovskaya, R., Coates, J., Polo, S., Miller, K. M., Jackson, S. P. Mammalian SUMO E3-ligases PIAS1 and PIAS4 promote responses to DNA double-strand breaks. Nature 462: 935-939, 2009. [PubMed: 20016603] [Full Text: https://doi.org/10.1038/nature08657]
Jones, M. C., Fusi, L., Higham, J. H., Abdel-Hafiz, H., Horwitz, K. B., Lam, E. W.-F., Brosens, J. J. Regulation of the SUMO pathway sensitizes differentiating human endometrial stromal cells to progesterone. Proc. Nat. Acad. Sci. 103: 16272-16277, 2006. [PubMed: 17053081] [Full Text: https://doi.org/10.1073/pnas.0603002103]
Kahyo, T., Nishida, T., Yasuda, H. Involvement of PIAS1 in the sumoylation of tumor suppressor p53. Molec. Cell 8: 713-718, 2001. [PubMed: 11583632] [Full Text: https://doi.org/10.1016/s1097-2765(01)00349-5]
Lee, H., Quinn, J. C., Prasanth, K. V., Swiss, V. A., Economides, K. D., Camacho, M. M., Spector, D. L., Abate-Shen, C. PIAS1 confers DNA-binding specificity on the Msx1 homeoprotein. Genes Dev. 20: 784-794, 2006. [PubMed: 16600910] [Full Text: https://doi.org/10.1101/gad.1392006]
Liu, B., Liao, J., Rao, X., Kushner, S. A., Chung, C. D., Chang, D. D., Shuai, K. Inhibition of Stat1-mediated gene activation by PIAS1. Proc. Nat. Acad. Sci. 95: 10626-10631, 1998. [PubMed: 9724754] [Full Text: https://doi.org/10.1073/pnas.95.18.10626]
Liu, B., Mink, S., Wong, K. A., Stein, N., Getman, C., Dempsey, P. W., Wu, H., Shuai, K. PIAS1 selectively inhibits interferon-inducible genes and is important in innate immunity. Nature Immun. 5: 891-898, 2004. [PubMed: 15311277] [Full Text: https://doi.org/10.1038/ni1104]
Liu, B., Tahk, S., Yee, K. M., Fan, G., Shuai, K. The ligase PIAS1 restricts natural regulatory T cell differentiation by epigenetic repression. Science 330: 521-525, 2010. [PubMed: 20966256] [Full Text: https://doi.org/10.1126/science.1193787]
Liu, B., Yang, Y., Chernishof, V., Loo, R. R. O., Jang, H., Tahk, S., Yang, R., Mink, S., Shultz, D., Bellone, C. J., Loo, J. A., Shuai, K. Proinflammatory stimuli induce IKK-alpha-mediated phosphorylation of PIAS1 to restrict inflammation and immunity. Cell 129: 903-914, 2007. [PubMed: 17540171] [Full Text: https://doi.org/10.1016/j.cell.2007.03.056]
Valdez, B. C., Henning, D., Perlaky, L., Busch, R. K., Busch, H. Cloning and characterization of Gu/RH-II binding protein. Biochem. Biophys. Res. Commun. 234: 335-340, 1997. [PubMed: 9177271] [Full Text: https://doi.org/10.1006/bbrc.1997.6642]
Weiskirchen, R., Moser, M., Weiskirchen, S., Erdel, M., Dahmen, S., Buettner, R., Gressner, A. M. LIM-domain protein cysteine- and glycine-rich protein 2 (CRP2) is a novel marker of hepatic stellate cells and binding partner of the protein inhibitor of activated STAT1. Biochem. J. 359: 485-496, 2001. [PubMed: 11672422] [Full Text: https://doi.org/10.1042/0264-6021:3590485]