Protein inhibitor of activated STAT (PIAS), also known as E3 SUMO-protein ligase PIAS, is a protein that regulates transcription in mammals. PIAS proteins act as transcriptional co-regulators with at least 60 different proteins in order to either activate or repress transcription. The transcription factors STAT, NF-κB, p73, and p53 are among the many proteins that PIAS interacts with. The seven proteins that belong to the mammalian PIAS family are encoded by four genes: PIAS1, PIAS2 (PIASx), PIAS3, and PIAS4 (PIASy). Apart from PIAS1, each gene encodes two protein isoforms. Homologues of PIAS proteins have been found in other eukaryotes, including Zimp/dPIAS in Drosophila melanogaster and zfPIAS4a in zebrafish. SIZ1 and SIZ2 were two homologues identified in yeast. PIAS proteins contain each conserved domain and motif of the PIAS protein family, with a few exceptions. The known functions of these domains and motifs are similar among all PIAS protein family members. These functions include acting as E3 SUMO-protein ligases during SUMOylation, which is an important process in transcriptional regulation. Presently, less is known about the higher order structure of PIAS proteins. The three-dimensional protein structures of PIAS2, PIAS3, and SIZ1 have only recently been solved. PIAS proteins have potential applications in cancer treatment and prevention. They may also play an important role in regulating immune system responses. Discovery The discovery of PIAS3 was first published in 1997. The discovery was made while the JAK-STAT pathway was being studied. The discovery of other PIAS proteins, including PIAS1, PIASxα, PIASxβ, and PIASy, was published the following year. The interaction between STATs and PIASs was characterized by the yeast two-hybrid assay. PIAS proteins were named based on their ability to inhibit STAT. For example, PIAS1 inhibited STAT1, and PIAS3 inhibited STAT3. When it was discovered that PIAS proteins did far more than simply inhibit STATs, it was proposed that the PIAS acronym should stand for Pleiotropic Interactors Associated with SUMO based on their association with SUMO proteins. Additionally, E3 SUMO-protein ligase PIAS is an alternative name for PIAS proteins. The discovery of PIAS3L, an isoform of PIAS3, was published in 2003. In addition, the discovery of PIASyE6- was published in 2004. It is an isoform of PIASy that doesn't contain exon 6. Types of PIAS proteins The table below lists the seven known proteins that belong to the mammalian PIAS protein family. Due to alternative splicing, some PIAS protein-encoding genes encode multiple protein products