Nedd4l, also known as Nedd4-2, is an E3 ubiquitin ligase that plays a crucial role in the ubiquitination process. Ubiquitination is a key protein post-translational modification, and Nedd4l participates in various biological processes by regulating protein degradation through ubiquitination. It is involved in pathways related to innate immunity, cardiovascular function, tumorigenesis, and intestinal homeostasis [1-3, 6]. Genetic models, such as gene knockout (KO) and conditional knockout (CKO) mouse models, are valuable for studying Nedd4l's functions.

In antiviral innate immunity, Nedd4l deficiency significantly impairs type I interferon and proinflammatory cytokine production induced by virus infection both in vitro and in vivo. It directly interacts with TRAF3 and catalyzes K29-linked ubiquitination of Cys56 and Cys124 in TRAF3, enhancing the association between TRAF3 and other E3 ligases and promoting type I interferon production [1].

In the context of intestinal homeostasis, global KO of Nedd4L or its deficiency in intestinal epithelial cells (IECs) exacerbates colitis and colorectal cancer induced by certain chemicals. Nedd4L deficiency in IECs inhibits the expression of the key ferroptosis regulator glutathione peroxidase 4 (GPX4) by reducing the protein expression of solute carrier family 3 member 2 (SLC3A2), promoting DSS-induced IEC ferroptosis [2].

In conclusion, Nedd4l is essential for maintaining normal biological functions in multiple systems. KO/CKO mouse models have revealed its significance in antiviral innate immunity and intestinal homeostasis, potentially providing insights into the development of treatments for related diseases such as viral infections, inflammatory bowel diseases, and colorectal cancer [1,2].