The gene codes for a protein of the PIAS family (protein inhibitor of activated STAT (signal transducer and activator of transcription)). PIAS3 regulates the activity of several transcription factors by direct protein-protein interaction. Further, PIAS3 is a SUMO (small ubiquitin-like modifier)-E3 ligase, catalyzing the covalent, post-translational modification of specific target proteins with SUMO. Different splice variants of PIAS3 have been identified but the full-length sequence of some of these variants has not been described.

The human PIAS3 gene is 10559 bp long and consists of 14 exons and 13 introns.

Transcript length 2902 bp (CDS 1887 bp ; residues 628 aa).

No pseudogene reported.

The human PIAS3 protein is a E3 SUMO-protein ligase consisting of 628 amino acids. It contains 5 conserved regions, the SAP, PINIT, SP-RING, SIM and S/T domains (figure 2).

PIAS3 is ubiquitously expressed.

Nuclear as well as cytoplasmic localization.

PIAS3 belongs to the mammalian protein inhibitor of activated STAT (PIAS) protein family, originally identified as cytokine-induced inhibitors of the STAT family of transcription factors. This protein class, referred to as SUMO-E3 ligases, increases the efficiency of SUMO conjugation. SUMO, a small ubiquitin-like modifier protein, is conjugated to a large number of cellular target proteins. Similar to enzymatic ubiquitination, the conjugation of specific SUMO proteins (SUMO-1-SUMO-3) to target proteins requires an E1-activating enzyme (Aos1/Uba2) as well as an E2-type SUMO-1-conjugating enzyme (Ubc9). Similar to many ubiquitin E3 ligases, these proteins contain a putative RING finger-like structure (SP-RING, figure 2), which is essential for their SUMO-E3 ligase activities toward various target proteins. Sumoylation is a dynamic process with highly diverse outcomes, ranging from changes in subcellular localization, signal transduction, transcriptional regulation to altered activity and stability of the modified protein. PIAS3 do, however, not only operate as SUMO-E3, since its coregulator effects are often independent of its RING-finger like domain but dependent on its capability to interact with sumoylated proteins via its conserved SIM (SUMO-interacting motif) or SAP (scaffold attachment factor-A/B/acinus/PIAS) domain (figure 2). Beside the N-terminal SAP, the SIM and the RING-type zinc-binding domain, a PINIT motif, and a serine/ threonine-rich C-terminal region (S/T) is conserved in PIAS3 (figure 2).
PIAS3 is involved in cytoplasmic regulation, such as functional interaction of PIAS3 with metabotropic glutamate receptor-8, voltage-gated potassium channel Kv1.5 and pyruvate kinase subtype M2, but the majority of so far reported interactions of the PIAS3 protein occurred with transcription factors or other proteins linked to nuclear regulation. PIAS3 can act in both transcriptional repression and activation. PIAS3 has been shown to repress STAT3 and Stat5 dependent transcriptional activation by blocking the DNA-binding of the factor without influencing its sumoylation. It interacts with and promotes sumoylation of the photoreceptor-specific transcription factor Nr2e3 when bound to specific promoters, which converts the factor to a transcriptional repressor. Moreover, PIAS3 was described as a repressor of microphthalmia transcription factor (MITF) and it was shown that PIAS3 blocks NF-kB mediated transcriptional activation by interacting with the p65/RelA subunit. Repression of IRF1-mediated transcription by PIAS3 has also been shown. PIAS3 has been shown to activate transcription mediated by Smad proteins through forming a complex with Smads and coactivator p300/CBP; moreover, PIAS proteins enhance steroid receptor-dependent transcription through an SP-RING-mediated interaction and sumoylation of the coactivator protein GRIP1/SCR2. Finally, PIAS3 was shown to modulate the ability of TIF2 to mediate ligand-enhanced transcription activation positively or negatively, for different steroid receptors.

The mammalian PIAS family consists of seven structurally related proteins (PIAS1, PIAS3, PIAS3b, PIASxa, PIASxb, PIASy, and PIASyE6) encoded by four genes. PIAS orthologs are found in nonvertebrate animal species, plants and yeasts.