Alternative titles; symbols
HGNC Approved Gene Symbol: PIAS4
Cytogenetic location: 19p13.3 Genomic coordinates (GRCh38) : 19:4,007,736-4,039,386 (from NCBI)
STAT proteins (e.g., STAT1; 600555) are latent cytoplasmic transcription factors that become activated by tyrosine phosphorylation in response to cytokine stimulation. Using a yeast 2-hybrid method to identify proteins that interact with STAT1, Liu et al. (1998) identified PIAS1 (protein inhibitor of activated STAT1; 603566). Using PIAS1 for database searches and cDNA library screening, they identified other related genes including PIASX (603567) and PIASY. PIASY encodes a deduced 510-amino acid protein. Like other members of the PIAS family, the predicted PIASY protein contains a putative zinc-binding motif and a highly acidic region.
Using GATA2 (137295) as bait in a yeast 2-hybrid screen of a placenta cDNA library, Chun et al. (2003) cloned PIASY. Northern blot analysis of several mouse tissues detected highest expression in testis. A similar expression pattern was observed in human tissues. Piasy was expressed in isolated mouse vascular endothelial cells and more weakly in smooth muscle cells and fibroblasts. Confocal microscopy detected PIASY in the nuclear compartment of transfected COS-1 cells, and deletion of its C-terminal half shifted PIASY to the cytoplasm.
Sachdev et al. (2001) determined that mammalian Piasy is a potent repressor of the Wnt (see 164820)-responsive transcription factor Lef1 (153245). Piasy stimulated the sumoylation of Lef1 and multiple other proteins in vivo and was a SUMO E3 ligase for Lef1 in a reconstituted system in vitro. Moreover, Piasy bound nuclear matrix-associated DNA sequences and targeted Lef1 to nuclear bodies. Sachdev et al. (2001) concluded that Piasy represses Lef1 by subnuclear sequestration.
By yeast 2-hybrid analysis, Chun et al. (2003) determined that PIASY interacts with GATA2, a transcription factor involved in hematopoietic and cardiovascular development. The binding required both the N- and C-terminal domains of PIASY, but not its central RING domain. PIASY enhanced the conjugation of SUMO2 (603042) to GATA2 through its E3 SUMO ligase activity. In a dose-dependent manner, cotransfection of PIASY suppressed GATA2-dependent ET1 (131240) promoter activity in bovine carotid endothelial cells. The suppressive effect required the GATA-binding site in the ET1 promoter and also depended upon the interaction between PIASY and GATA2. Stimulation of bovine carotid endothelial cells with VEGF (192240), BFGF (134920), or fetal calf serum stimulated endogenous Piasy expression. Chun et al. (2003) concluded that PIASY enhances the conjugation of SUMO2 to GATA2 and that the interaction of PIASY with GATA2 can modulate GATA-mediated ET1 transcription in endothelial cells through a mechanism that does not require the RING-like domain.
Galanty et al. (2009) demonstrated that SUMO1 (601912), 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 and PIAS1 (603566). 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.
Scott (2000) mapped the PIASY gene to chromosome 19 based on sequence similarity between the PIASY sequence (GenBank AF077952) and a chromosome 19 clone (GenBank AC016586).
The article by Bischof et al. (2006) on the function of PIASY was retracted because of irregularities in the Western blots and incorrect data use in several figures.
Bischof, O., Schwamborn, K., Martin, N., Werner, A., Sustmann, C., Grosschedl, R., Dejean, A. The E3 SUMO ligase PIASy is a regulator of cellular senescence and apoptosis. Molec. Cell 22: 783-794, 2006. Note: Retraction. Molec. Cell 80: 1140 only, 2020. [PubMed: 16793547] [Full Text: https://doi.org/10.1016/j.molcel.2006.05.016]
Chun, T.-H., Itoh, H., Subramanian, L., Iniguez-Lluhi, J. A., Nakao, K. Modification of GATA-2 transcriptional activity in endothelial cells by the SUMO E3 ligase PIASy. Circ. Res. 92: 1201-1208, 2003. [PubMed: 12750312] [Full Text: https://doi.org/10.1161/01.RES.0000076893.70898.36]
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]
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]
Sachdev, S., Bruhn, L., Sieber, H., Pichler, A., Melchior, F., Grosschedl, R. PIASy, a nuclear matrix-associated SUMO E3 ligase, represses LEF1 activity by sequestration into nuclear bodies. Genes Dev. 15: 3088-3103, 2001. [PubMed: 11731474] [Full Text: https://doi.org/10.1101/gad.944801]
Scott, A. F. Personal Communication. Baltimore, Md. 7/16/2000.