Nedd4l, also known as Nedd4-2, is an E3 ubiquitin ligase belonging to the Nedd4 family. Ubiquitination, a key protein post-translational modification, is essential for regulating the expression level and function of cellular proteins, and Nedd4l plays a significant role in this process [2]. It is involved in multiple biological processes and diseases, with its functions affecting various signaling pathways.

In antiviral immunity, Nedd4l deficiency significantly impairs type I interferon and proinflammatory cytokine production induced by virus infection both in vitro and in vivo. Nedd4l positively regulates antiviral immunity by catalyzing K29-linked cysteine ubiquitination of TRAF3, which affects the binding between TRAF3 and TBK1, and subsequent phosphorylation of TBK1 and IRF3 [1]. In the cardiovascular field, although its role is not fully understood, it is known to participate in various pathophysiological processes of cardiovascular diseases such as hypertension, myocardial hypertrophy, and heart failure [2]. In tumors, Nedd4l plays dual roles. In esophageal carcinoma, its low expression is related to tumor progression, and it suppresses the growth and metastasis of esophageal carcinoma by mediating ITGB4 ubiquitination and degradation [3]. In colorectal carcinoma, circNEIL3 recruits Nedd4l to degrade YBX1, thus inhibiting tumor metastasis [4]. In the intestine, NEDD4L deficiency in intestinal epithelial cells (IECs) exacerbates colitis and colorectal tumorigenesis, as it inhibits the expression of the key ferroptosis regulator GPX4, promoting IEC ferroptosis [5]. In the context of high-fat diet-induced lung fibrosis, p16 accumulation in aging cells inhibits NEDD4L-mediated K48-polyubiquitin-dependent degradation of SGK1, aggravating fibrosis [6]. In pancreatic cancer, LINC00941 promotes malignancy by suppressing NEDD4L-mediated degradation of ANXA2 [8]. In the heart, Nedd4l's intramolecular interactions regulate its auto and substrate NaV1.5 ubiquitination, which is crucial for cardiac function as alterations in Na+ current are involved in cardiac diseases [7].

In conclusion, Nedd4l is a vital E3 ubiquitin ligase involved in multiple biological processes and diseases. Through gene knockout (KO) or conditional knockout (CKO) mouse models and other loss-of-function experiments, its role in antiviral immunity, cardiovascular diseases, tumorigenesis, intestinal homeostasis, and lung fibrosis has been revealed. These findings contribute to understanding the mechanisms of these diseases and may provide potential therapeutic targets.

References:

1. Gao, Peng, Ma, Xianwei, Yuan, Ming, Yuan, Hongbin, An, Huazhang. 2021. E3 ligase Nedd4l promotes antiviral innate immunity by catalyzing K29-linked cysteine ubiquitination of TRAF3. In Nature communications, 12, 1194. doi:10.1038/s41467-021-21456-1. https://pubmed.ncbi.nlm.nih.gov/33608556/

2. Li, Mohan, Sun, Guozhe, Wang, Pengbo, Zhang, Ying, Zhang, Naijin. 2022. Research progress of Nedd4L in cardiovascular diseases. In Cell death discovery, 8, 206. doi:10.1038/s41420-022-01017-1. https://pubmed.ncbi.nlm.nih.gov/35429991/

3. Shi, Yijun, Fang, Na, Wu, Yutong, Chu, Minjie, Cui, Jiahua. 2024. NEDD4L mediates ITGB4 ubiquitination and degradation to suppress esophageal carcinoma progression. In Cell communication and signaling : CCS, 22, 302. doi:10.1186/s12964-024-01685-9. https://pubmed.ncbi.nlm.nih.gov/38831335/

4. Chen, Shuang, Li, Ke, Guo, Jiawei, Xu, Heng, Peng, Yong. 2023. circNEIL3 inhibits tumor metastasis through recruiting the E3 ubiquitin ligase Nedd4L to degrade YBX1. In Proceedings of the National Academy of Sciences of the United States of America, 120, e2215132120. doi:10.1073/pnas.2215132120. https://pubmed.ncbi.nlm.nih.gov/36961927/

5. Liang, Jingjing, Wang, Ning, Yao, Yihan, Wang, Xiaojian, Lin, Wenlong. 2024. NEDD4L mediates intestinal epithelial cell ferroptosis to restrict inflammatory bowel diseases and colorectal tumorigenesis. In The Journal of clinical investigation, 135, . doi:10.1172/JCI173994. https://pubmed.ncbi.nlm.nih.gov/39688910/

6. Gu, Xin, Meng, Haoyu, Peng, Chengyi, Jin, Jianliang, Wang, Xiaoyan. . Inflammasome activation and metabolic remodelling in p16-positive aging cells aggravates high-fat diet-induced lung fibrosis by inhibiting NEDD4L-mediated K48-polyubiquitin-dependent degradation of SGK1. In Clinical and translational medicine, 13, e1308. doi:10.1002/ctm2.1308. https://pubmed.ncbi.nlm.nih.gov/37345264/

7. Wright, Katharine M, Nathan, Sara, Jiang, Hanjie, Cole, Philip A, Gabelli, Sandra B. 2024. NEDD4L intramolecular interactions regulate its auto and substrate NaV1.5 ubiquitination. In The Journal of biological chemistry, 300, 105715. doi:10.1016/j.jbc.2024.105715. https://pubmed.ncbi.nlm.nih.gov/38309503/

8. Wang, Jie, He, Zhiwei, Liu, Xinyuan, Quan, Gang, Jiang, Jianxin. 2022. LINC00941 promotes pancreatic cancer malignancy by interacting with ANXA2 and suppressing NEDD4L-mediated degradation of ANXA2. In Cell death & disease, 13, 718. doi:10.1038/s41419-022-05172-2. https://pubmed.ncbi.nlm.nih.gov/35977942/