Pja2, also known as praja ring finger ubiquitin ligase 2, is an E3 ubiquitin ligase. It plays crucial roles in multiple biological processes by regulating protein ubiquitination. It is involved in pathways such as type I interferon signaling, Wnt/β -catenin signaling, and is associated with cellular functions like cell differentiation, apoptosis, and tumor progression [1,3]. Genetic models, especially KO/CKO mouse models, can be valuable for studying its functions in vivo.

In type I interferon signaling, Pja2 acts as a negative regulator. It interacts with TYK2 and JAK1, promotes their non-degradative ubiquitination, and limits TYK2 activating phosphorylation, restraining downstream STAT signaling [1]. In colorectal cancer, Pja2 is downregulated, and its decreased expression correlates with poor prognosis. Functionally, it inhibits tumor cell proliferation and promotes apoptosis. Mechanistically, it recognizes histone deacetylase 2 (HDAC2) and facilitates its ubiquitination and degradation, counteracting the transcriptional repression of the IFIT family [2]. Pja2 also inhibits Wnt/β -catenin signaling by binding to TCF/LEF1, ubiquitinating them, and reducing their levels, thus regulating stem cell differentiation [3]. In pancreatic β-cells, the SIK2-p35-PJA2 complex is essential for glucose homeostasis and insulin secretion [4].

In summary, Pja2 is an important E3 ubiquitin ligase involved in multiple biological processes and diseases. Through model-based research, especially KO/CKO mouse models (if applicable in the future), we have gained insights into its role in type I interferon signaling regulation, colorectal cancer suppression, stem cell differentiation, and pancreatic β-cell function. These findings contribute to understanding the underlying mechanisms of these biological processes and disease conditions, potentially providing new targets for therapeutic intervention.

References:

1. Schiefer, Samira, Hale, Benjamin G. 2024. Proximal protein landscapes of the type I interferon signaling cascade reveal negative regulation by PJA2. In Nature communications, 15, 4484. doi:10.1038/s41467-024-48800-5. https://pubmed.ncbi.nlm.nih.gov/38802340/

2. Chen, Zhihao, Peng, Chaofan, Jin, Chi, Sun, Yueming, Feng, Yifei. 2025. PJA2 Suppresses Colorectal Cancer Progression by Controlling HDAC2 Degradation and Stability. In Advanced science (Weinheim, Baden-Wurttemberg, Germany), 12, e2401964. doi:10.1002/advs.202401964. https://pubmed.ncbi.nlm.nih.gov/39928532/

3. Song, Yonghee, Lee, Somyung, Kim, Jeong-Rae, Jho, Eek-Hoon. . Pja2 Inhibits Wnt/β-catenin Signaling by Reducing the Level of TCF/LEF1. In International journal of stem cells, 11, 242-247. doi:10.15283/ijsc18032. https://pubmed.ncbi.nlm.nih.gov/30021253/

4. Sakamaki, Jun-Ichi, Fu, Accalia, Reeks, Courtney, Yee, Siu-Pok, Screaton, Robert A. . Role of the SIK2-p35-PJA2 complex in pancreatic β-cell functional compensation. In Nature cell biology, 16, 234-44. doi:10.1038/ncb2919. https://pubmed.ncbi.nlm.nih.gov/24561619/