PIAS2, short for Protein Inhibitor of Activated STAT 2, is a key modulator in multiple biological pathways. It belongs to the PIAS protein family which are important signal transduction modulators, regulating innate immune signaling pathways such as those involving NF-κB, IRF3, and JAK/STAT. PIAS2 also functions as a SUMO E3 ligase, playing a role in the SUMOylation process which can impact protein function, localization, and stability [2,3,5,6].

In the context of disease, in sporadic Parkinson disease dementia (sPDD), increased PIAS2 expression was found to be associated with defective neuronal IFNβ-IFNAR signaling. Overexpressing PIAS2 in mouse brains led to motor and cognitive impairments, intraneuronal phosphorylated α-synuclein accumulation, and dopaminergic neuron loss. Conversely, PIAS2 knockdown in Ifnb-/- mice rescued the clinicopathological manifestations of PDD by restoring mitochondrial homeostasis, oxidative stress, and pERK1/2-pP53 signaling [1]. In ducks, duPIAS2 negatively regulates RIG-I mediated IFN-β production by interacting with IRF7 [2], and promotes H5N1 avian influenza virus replication through its SUMO E3 ligase activity by interacting with the viral nucleoprotein [3]. In anaplastic carcinomas, depletion of the PIAS2β isoform specifically inhibits growth, as PIAS2β is required for proper mitotic spindle and centrosome assembly [4].

In conclusion, PIAS2 is a crucial regulator in multiple biological processes and disease conditions. Studies using mouse models, especially those with PIAS2 manipulation, have revealed its role in neurodegenerative diseases like sPDD, antiviral immune responses in ducks, and the growth regulation of anaplastic carcinomas. Understanding PIAS2 can potentially offer new therapeutic approaches for these diseases.

References:

1. Magalhaes, Joana, Tresse, Emilie, Ejlerskov, Patrick, Gasser, Thomas, Issazadeh-Navikas, Shohreh. 2021. PIAS2-mediated blockade of IFN-β signaling: a basis for sporadic Parkinson disease dementia. In Molecular psychiatry, 26, 6083-6099. doi:10.1038/s41380-021-01207-w. https://pubmed.ncbi.nlm.nih.gov/34234281/

2. Zu, Shaopo, Xue, Qian, He, Zhuoliang, Jiao, Peirong, Liao, Ming. 2020. Duck PIAS2 negatively regulates RIG-I mediated IFN-β production by interacting with IRF7. In Developmental and comparative immunology, 108, 103664. doi:10.1016/j.dci.2020.103664. https://pubmed.ncbi.nlm.nih.gov/32151676/

3. Zu, Shaopo, Xue, Qian, He, Zhuoliang, Jiao, Peirong, Liao, Ming. 2020. Duck PIAS2 Promotes H5N1 Avian Influenza Virus Replication Through Its SUMO E3 Ligase Activity. In Frontiers in microbiology, 11, 1246. doi:10.3389/fmicb.2020.01246. https://pubmed.ncbi.nlm.nih.gov/32595623/

4. Rodrigues, Joana S, Chenlo, Miguel, Bravo, Susana B, Cameselle-Teijeiro, José Manuel, Alvarez, Clara V. 2024. dsRNAi-mediated silencing of PIAS2beta specifically kills anaplastic carcinomas by mitotic catastrophe. In Nature communications, 15, 3736. doi:10.1038/s41467-024-47751-1. https://pubmed.ncbi.nlm.nih.gov/38744818/

5. Du, Junfeng, Du, Yujia, Chen, Lang, Liu, Hongwei. 2023. IL-17 promotes melanoma through TRAF2 as a scaffold protein recruiting PIAS2 and ELAVL1 to induce EPHA5. In Biochimica et biophysica acta. Molecular cell research, 1870, 119547. doi:10.1016/j.bbamcr.2023.119547. https://pubmed.ncbi.nlm.nih.gov/37481078/

6. Salas-Lloret, Daniel, Jansen, Nicolette S, Nagamalleswari, Easa, Vertegaal, Alfred C O, González-Prieto, Román. 2023. SUMO-activated target traps (SATTs) enable the identification of a comprehensive E3-specific SUMO proteome. In Science advances, 9, eadh2073. doi:10.1126/sciadv.adh2073. https://pubmed.ncbi.nlm.nih.gov/37531430/