WWP2, an E3 ubiquitin ligase, plays a crucial role in regulating numerous cellular biological activities. It exerts its function through the ubiquitination and degradation of its substrates, participating in various pathways such as the PTEN/Akt signaling pathway. This gene is of great biological importance as it is involved in processes like DNA repair, gene expression, signal transduction, and cell-fate decisions, and is thus linked to normal physiology and various diseases [1,8].

In different disease models, WWP2 shows distinct functions. In cardiac remodeling, myocardial-specific knockout of WWP2 decreased PARP1 ubiquitination, aggravating isoproterenol-induced myocardial hypertrophy, heart failure, and fibrosis, suggesting its role in regulating cardiac remodeling through the WWP2-PARP1 pathway [2]. In renal fibrosis, WWP2 deficiency promoted myofibroblast proliferation while halting profibrotic activation, reducing the severity of renal fibrosis in vivo, and it regulated the metabolic reprogramming of profibrotic myofibroblasts via the WWP2-PGC-1α axis [3]. In heart fibrosis, myeloid-specific deletion of WWP2 reduced cardiac fibrosis in hypertension-induced non-ischemic cardiomyopathy by affecting pro-fibrogenic Ly6chigh monocytes [4]. In Type 2 diabetes mellitus-induced vascular endothelial injury, endothelial-specific knockout of Wwp2 in mice aggravated the injury, indicating that down-regulation of WWP2 exacerbates this condition [5]. In breast cancer, lncRNA BREA2 promotes metastasis by disrupting the WWP2-mediated ubiquitination of Notch1 [6]. In sepsis-induced cardiac injury, cardiac-specific overexpression of WWP2 protected the heart from injury, while knockdown or knockout exacerbated the process, with WWP2 acting by suppressing cardiomyocyte ferroptosis [7].

In conclusion, WWP2 is a key regulator in multiple biological processes and diseases. Gene knockout and conditional knockout mouse models have been instrumental in revealing its functions in areas such as cardiac remodeling, renal fibrosis, heart fibrosis, vascular endothelial injury, breast cancer metastasis, and sepsis-induced cardiac injury. Understanding WWP2 provides insights into disease mechanisms and potential therapeutic targets.

References:

1. Zhang, Rui, Zhang, Jianwu, Luo, Wei, Luo, Zhuang, Shi, Shaoqing. 2018. WWP2 Is One Promising Novel Oncogene. In Pathology oncology research : POR, 25, 443-446. doi:10.1007/s12253-018-0506-5. https://pubmed.ncbi.nlm.nih.gov/30415470/

2. Zhang, Naijin, Zhang, Ying, Qian, Hao, Cao, Liu, Sun, Yingxian. 2020. Selective targeting of ubiquitination and degradation of PARP1 by E3 ubiquitin ligase WWP2 regulates isoproterenol-induced cardiac remodeling. In Cell death and differentiation, 27, 2605-2619. doi:10.1038/s41418-020-0523-2. https://pubmed.ncbi.nlm.nih.gov/32139900/

3. Chen, Huimei, You, Ran, Guo, Jing, Zhang, Aihua, Petretto, Enrico. 2024. WWP2 Regulates Renal Fibrosis and the Metabolic Reprogramming of Profibrotic Myofibroblasts. In Journal of the American Society of Nephrology : JASN, 35, 696-718. doi:10.1681/ASN.0000000000000328. https://pubmed.ncbi.nlm.nih.gov/38502123/

4. Chen, Huimei, Chew, Gabriel, Devapragash, Nithya, Behmoaras, Jacques, Petretto, Enrico. 2022. The E3 ubiquitin ligase WWP2 regulates pro-fibrogenic monocyte infiltration and activity in heart fibrosis. In Nature communications, 13, 7375. doi:10.1038/s41467-022-34971-6. https://pubmed.ncbi.nlm.nih.gov/36450710/

5. You, Shilong, Xu, Jiaqi, Yin, Zeyu, Sun, Yingxian, Zhang, Naijin. 2023. Down-regulation of WWP2 aggravates Type 2 diabetes mellitus-induced vascular endothelial injury through modulating ubiquitination and degradation of DDX3X. In Cardiovascular diabetology, 22, 107. doi:10.1186/s12933-023-01818-3. https://pubmed.ncbi.nlm.nih.gov/37149668/

6. Zhang, Zhen, Lu, Yun-Xin, Liu, Fangzhou, Li, Xu, Lin, Aifu. 2023. lncRNA BREA2 promotes metastasis by disrupting the WWP2-mediated ubiquitination of Notch1. In Proceedings of the National Academy of Sciences of the United States of America, 120, e2206694120. doi:10.1073/pnas.2206694120. https://pubmed.ncbi.nlm.nih.gov/36795754/

7. Li, Zhi, Wu, Boquan, Chen, Jie, Zhang, Xingang, Sun, Guozhe. 2024. WWP2 protects against sepsis-induced cardiac injury through inhibiting cardiomyocyte ferroptosis. In Journal of translational internal medicine, 12, 35-50. doi:10.2478/jtim-2024-0004. https://pubmed.ncbi.nlm.nih.gov/38591063/

8. You, Shilong, Xu, Jiaqi, Guo, Yushan, Sun, Guozhe, Sun, Yingxian. 2024. E3 ubiquitin ligase WWP2 as a promising therapeutic target for diverse human diseases. In Molecular aspects of medicine, 96, 101257. doi:10.1016/j.mam.2024.101257. https://pubmed.ncbi.nlm.nih.gov/38430667/