Ube3c, an E3 ubiquitin ligase, plays crucial roles in multiple biological processes. It is involved in pathways such as autophagy, endoplasmic reticulum-associated degradation (ERAD), and the Wnt/β-catenin signaling pathway. Ubiquitination, a post-translational modification it mediates, is key to regulating protein stability and function, thus impacting various cellular functions and overall biological importance. Genetic models, like KO mouse models, are valuable for studying its functions.

In autophagy, Ube3c was identified as a new E3 ligase of ATG4B. It assembles K33-branched ubiquitin chains on ATG4B at Lys119, inhibiting autophagy flux without causing ATG4B degradation [1]. In ER-associated degradation, Ube3c facilitates the ERAD of misfolded CFTR and ABCB1, and may be involved in maintaining the peripheral quality control of CFTR [2]. In head and neck cancer, the UBE3C-LRP5 translocation promotes cell proliferation, migration, and invasion by activating the Wnt/β-catenin signaling pathway [3]. In EV-A71 infection, Ube3c restricts viral replication by ubiquitination-dependent degradation of 2C protein [4]. In breast cancer, Ube3c acts as an oncogenic factor, promoting cell growth and metastasis by activating the Wnt/β-catenin signaling pathway [5]. In the uterus, Ube3c targets PR for polyubiquitination and proteasome degradation in the absence of P38α, affecting uterine progesterone responsiveness [6]. In gastric cancer, Ube3c promotes cell proliferation and inhibits apoptosis by activating the β-catenin signaling via degradation of AXIN1 [7]. In clear cell renal cell carcinoma, circPOLR2A enhances the UBE3C-mediated ubiquitination and degradation of the PEBP1 protein, activating the ERK signaling pathway [8].

In conclusion, Ube3c is essential in regulating multiple biological processes through its ubiquitination-related functions. Its role in various diseases, including cancers, viral infections, and uterine function-related disorders, has been revealed through model-based research. The study of Ube3c KO/CKO mouse models has provided insights into these disease-associated mechanisms, highlighting its potential as a therapeutic target in these disease areas.