Protein inhibitor of activated STAT

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. 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. == Types of PIAS proteins ==

of SIZ1. SIZ1 is a PIAS protein homologue found in yeast. 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 called isoforms. PIAS1 is the only gene of this family that does not encode any isoforms. • zfPIAS4a in zebrafish • SIZ1 and SIZ2 in yeast == Function ==

PIAS proteins contribute to the control of gene expression, and may be considered transcriptional co-regulators. While PIAS proteins interact with at least 60 different proteins involved in transcription, For example, the activity of transcription factor p73 was repressed after it was SUMOylated by PIAS1. One function of PIAS proteins is to relocate transcriptional regulators to different compartments within the nucleus of the cell. Additionally, PIAS proteins are important transcriptional co-regulators of the JAK/STAT signaling pathway. PIAS protein's interaction with STAT signaling requires tyrosine phosphorylation of STAT proteins. Additionally, PIAS1 binds preferentially to un-methylated STAT1. PIAS3 was found to specifically inhibit STAT3 signaling after stimulation by the cytokine IL-6. Also, it is known that PIAS1 can inhibit NF-κB activity upon stimulation by the cytokine TNF and the LPS endotoxin. == Structure ==

The three-dimensional protein structures of PIAS2, PIAS3, and PIAS-like protein SIZ1 were recently solved using X-ray crystallography. The structures of PIAS2 and PIAS3 were listed in the Structural Genomics Consortium in 2012 and 2013, respectively, by A. Dong et al. Details of the SIZ1 structure were published by Ali A. Yunus and Christopher D. Lima in 2009. Four PIAS domains and two PIAS motifs have been identified. They include the N-terminal scaffold attachment factor-A/B, acinus and PIAS (SAP) domain, the Pro-Ile-Asn-Ile-Thr (PINIT) motif, the RING-finger-like zinc-binding domain (RLD), the highly acidic domain (AD), the SUMO-interacting motif (SIM), and the serine/threonine-rich C-terminal region (S/T). SAP The N-terminal scaffold attachment factor-A/B, acinus and PIAS (SAP) domain is found in all PIAS proteins. It binds to areas of chromatin that are rich in adenine (A) and thymine (T). These A/T rich regions are known as matrix-attachment regions. Once bound, the matrix-attachment regions anchor loops of chromatin to the nuclear matrix. The nuclear matrix is a structure within the nucleus where it is thought that transcription regulation takes place. PINIT The Pro-Ile-Asn-Ile-Thr (PINIT) motif was discovered in PIAS3L, an isoform of PIAS3. PIAS proteins tend to go back and forth between the nucleus and cytosol as they carry out their activities. PINIT is needed to localize PIAS3 and PIAS3L to the nucleus. PIASy has a slight difference in its PINIT motif: leucine is in place of the second isoleucine (PINLT). Furthermore, the PINIT motif is not found in PIASy isoform PIASyE6-. This isoform, lacking exon 6, is still retained in the nucleus despite lacking the PINIT motif. The reason for this is unknown. RLD The RING-finger-like zinc-binding domain is present in all PIAS proteins. RLD is essential for PIAS proteins to function as E3 SUMO-protein ligases. It is also needed for successful interaction with other proteins. Its three dimensional structure is thought to be similar to typical RING finger domains. It contains one histidine residue and five cysteine residues AD and SIM The highly acidic domain (AD), present in all PIAS proteins, contains a SUMO-interacting motif (SIM). The SIM motif may be needed for PIAS proteins to accurately recognize and interact with other SUMO proteins. However, it is not needed for E3 SUMO-protein ligase activity to occur. The function of the highly acidic domain is unknown. S/T The Serine/threonine-rich C-terminal (S/T) region is not found in all PIAS proteins. PIASy and PIASyE6- are the only members of the PIAS protein family that lack this region. Furthermore, the length of this region varies among PIAS protein isoforms. The function of the S/T region is unknown. == Potential applications ==

Defects in the DNA repair system lead to a predisposition for developing cancer. At least some of the PIAS proteins are implicated in DNA repair, and specifically in enhancing repair of double-stranded breaks. In cell culture, overexpression of PIAS3 demonstrated an increased resistance of HeLa cells to ionizing radiation. While inhibition of PIAS by siRNAs led cancer cells to accelerate cell proliferation and demonstrate higher levels of resistance to chemotherapy drugs. In a study of human brain tissue samples from glioblastoma multiforme patients, PIAS3 expression was found to be reduced compared to the control brain tissue. Inhibition of PIAS3 resulted in increased glioblastoma propagation, while PIAS3 overexpression inhibited STAT-3 signaling and cell proliferation . Furthermore, patients with higher levels of BRCA1, PIAS1, and PIAS4 survived for a longer period of time in a retrospective study of advanced gastric cancer patients. Continuous activation of the JAK-STAT pathway can cause cancer in humans as well as less complex organisms such as Drosophila. Given the preliminary evidence and their effects on important signaling pathways involved in cancer, PIAS proteins may be interesting targets for the development of treatments for cancers or as sensitizers for chemotherapeutic drugs and radiation in BRCA-deficient cancers. Clinical proof of concept for the use of JAK inhibitors for treatment of autoimmune and inflammatory disease has been demonstrated by Pfizer's tofacitinib, a JAK inhibitor recently approved in the US for the treatment of rheumatoid arthritis. Additionally, tofacitinib is currently being studied for the treatment of ankylosing spondylitis, psoriatic arthritis, psoriasis, atopic dermatitis, and inflammatory bowel disease. Furthermore, STAT1 and STAT2 are essential factors in the cellular antiviral and adaptive immune defenses. PIAS proteins and other regulators are necessary for homeostasis and for fine tuning the immune response. PIAS proteins regulate STAT transcription through several mechanisms, and genetic studies in rodents have shown that PIAS1 plays an important physiological role in STAT1 regulation. Many of the 60 proteins that PIAS protein family is believed to interact with are immune regulatory factors. == References ==