Pja1, encoding a RING-H2 finger ubiquitin ligase, is a gene located on human chromosome Xq12 and is abundantly expressed in the brain [7]. As an E3 ubiquitin ligase, it is involved in protein ubiquitination, which can regulate various cellular processes such as the degradation of specific proteins. It is associated with pathways like the CREB signaling pathway, TGF-β signaling, and is also related to immune responses against DNA viruses [1,3,6].

In female mice, astrocytic GPR30 positively modulates Pja1 expression through the CREB signaling pathway, and Pja1 mediates the effects of astrocytic GPR30 on learning and memory by binding to Serpina3n, suggesting its role in menopausal-related learning and memory decline [1]. In nasopharyngeal carcinoma, high Pja1 expression is linked to docetaxel resistance as it inhibits GSDME-mediated pyroptosis. Knockdown of Pja1 or targeting it with the inhibitor RTA402 restores docetaxel sensitivity [2]. In liver cancers, Pja1 overexpression suppresses SMAD3-and SPTBN1-mediated TGF-β tumor suppressor signaling, promoting HCC proliferation, and inhibition of Pja1 can restore TGF-β tumor-suppressor function [3,5]. Pja1 knockout mice display moderate deficits in isolation-induced ultrasonic vocalizations and increased seizure susceptibility, indicating its role in neurodevelopmental disorders [4].

In summary, Pja1 plays crucial roles in multiple biological processes and disease conditions. Gene knockout mouse models have been instrumental in revealing its functions in learning and memory, chemoresistance in cancer, and neurodevelopmental disorders. Understanding Pja1 provides potential therapeutic targets for menopausal-related cognitive decline, nasopharyngeal carcinoma, liver cancer, and neurodevelopmental disorders.

References:

1. Wang, Xinshang, Jiang, Yongli, Feng, Ban, Zhao, Minggao, Liu, Shuibing. 2023. PJA1 mediates the effects of astrocytic GPR30 on learning and memory in female mice. In The Journal of clinical investigation, 133, . doi:10.1172/JCI165812. https://pubmed.ncbi.nlm.nih.gov/37712419/

2. Huang, Sheng-Yan, Gong, Sha, Zhao, Yin, Li, Ying-Qing, Liu, Na. 2024. PJA1-mediated suppression of pyroptosis as a driver of docetaxel resistance in nasopharyngeal carcinoma. In Nature communications, 15, 5300. doi:10.1038/s41467-024-49675-2. https://pubmed.ncbi.nlm.nih.gov/38906860/

3. Chen, Jian, A Gingold, Julian. 2020. Dysregulated PJA1-TGF-β signaling in cancer stem cell-associated liver cancers. In Oncoscience, 7, 88-95. doi:10.18632/oncoscience.522. https://pubmed.ncbi.nlm.nih.gov/33457451/

4. Suzuki, Toshimitsu, Suzuki, Toshifumi, Raveau, Matthieu, Matsumoto, Naomichi, Yamakawa, Kazuhiro. 2020. A recurrent PJA1 variant in trigonocephaly and neurodevelopmental disorders. In Annals of clinical and translational neurology, 7, 1117-1131. doi:10.1002/acn3.51093. https://pubmed.ncbi.nlm.nih.gov/32530565/

5. Chen, Jian, Mitra, Abhisek, Li, Shulin, Wu, Ray-Chang, Mishra, Lopa. 2020. Targeting the E3 Ubiquitin Ligase PJA1 Enhances Tumor-Suppressing TGFβ Signaling. In Cancer research, 80, 1819-1832. doi:10.1158/0008-5472.CAN-19-3116. https://pubmed.ncbi.nlm.nih.gov/32127355/

6. Xu, Wei, Ma, Chunqiang, Zhang, Qi, Liu, Yingle, Wu, Jianguo. 2018. PJA1 Coordinates with the SMC5/6 Complex To Restrict DNA Viruses and Episomal Genes in an Interferon-Independent Manner. In Journal of virology, 92, . doi:10.1128/JVI.00825-18. https://pubmed.ncbi.nlm.nih.gov/30185588/

7. Yu, Ping, Chen, Yiwang, Tagle, Danilo A, Cai, Tao. . PJA1, encoding a RING-H2 finger ubiquitin ligase, is a novel human X chromosome gene abundantly expressed in brain. In Genomics, 79, 869-74. doi:. https://pubmed.ncbi.nlm.nih.gov/12036302/