- UBE2L3 (Ubiquitin-conjugating enzyme E2 L3), also known as UBCH7, is a highly conserved member of the ubiquitin-conjugating enzyme (E2) family that plays a central role in diverse cellular processes by mediating ubiquitination.
- Like other E2 enzymes, UBE2L3 functions by accepting activated ubiquitin from an E1 ubiquitin-activating enzyme and collaborating with an E3 ubiquitin ligase to transfer ubiquitin to target proteins. What distinguishes UBE2L3 is its ability to interact with a broad range of E3 ligases, including both HECT-type and RING-type ligases, giving it wide functional versatility.
- One of UBE2L3’s most important roles lies in the regulation of immune signaling. It has been implicated in the NF-κB pathway, where it contributes to the ubiquitination of components such as IκBα, thereby controlling NF-κB activation and downstream transcription of inflammatory genes. UBE2L3 also participates in TNF receptor and T-cell receptor signaling, as well as in the ubiquitination of immune-related kinases. Through these functions, it serves as a critical modulator of immune homeostasis. Genetic studies have further highlighted this role: variants in UBE2L3 are associated with increased risk of autoimmune diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis, Crohn’s disease, and type 1 diabetes. These associations suggest that subtle changes in UBE2L3 activity can shift the balance of immune regulation toward pathological inflammation.
- Beyond immunity, UBE2L3 also participates in cell cycle control, apoptosis, and DNA repair. It regulates the turnover of transcription factors and cell cycle regulators, influencing proliferation and cell survival. Its broad E3 ligase partnerships allow it to target multiple signaling pathways, which makes UBE2L3 a hub in cellular decision-making. For example, it has been shown to interact with the tumor suppressor p53 pathway and with regulators of apoptosis, linking it to both cancer suppression and progression depending on cellular context.
- Clinically, dysregulation of UBE2L3 is relevant not only in autoimmunity but also in oncology. Elevated expression of UBE2L3 has been observed in several cancers, where it may promote tumor growth by facilitating degradation of tumor suppressors or enhancing survival signaling. Conversely, its loss or dysfunction could impair immune surveillance or DNA repair, predisposing cells to malignant transformation. Because of these diverse connections, UBE2L3 is being explored as a potential therapeutic target in both autoimmune and cancer research.
- Structurally, UBE2L3 contains the characteristic ubiquitin-conjugating (UBC) catalytic domain, with an active-site cysteine that forms a thioester bond with ubiquitin. Unlike some E2s that strongly favor K48- or K63-linked chain formation, UBE2L3 is flexible in chain topology, depending on its E3 partner. This adaptability underlies its functional diversity but also makes it more challenging to study in terms of substrate specificity.
- In summary, UBE2L3 is a versatile ubiquitin-conjugating enzyme that connects the ubiquitin system to immunity, cell cycle regulation, apoptosis, and cancer biology. Genetic variants highlight its key role in autoimmune disease susceptibility, while dysregulated expression links it to tumorigenesis. Its broad interactions with E3 ligases make it a central node in ubiquitin signaling networks, and ongoing research is focused on exploiting this enzyme as a therapeutic target in immune-mediated and malignant disorders.
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