- UBE2N (Ubiquitin-conjugating enzyme E2 N), also known as Ubc13, is a ubiquitin-conjugating enzyme (E2) that plays a specialized role in forming K63-linked polyubiquitin chains.
- Unlike K48-linked chains, which usually signal for proteasomal degradation, K63-linked ubiquitination functions primarily in non-proteolytic signaling pathways, such as DNA damage repair, innate immune signaling, and inflammation. Because of this, UBE2N serves as a critical regulator of cellular stress responses, genome stability, and immune defense.
- UBE2N does not work alone—it requires a cofactor, either UBE2V1 (Uev1A) or UBE2V2 (MMS2). These are ubiquitin-conjugating enzyme variants (UEVs) that lack the active-site cysteine necessary to form a thioester bond with ubiquitin. Instead, they act as regulatory partners that guide UBE2N to build specific ubiquitin chain linkages. Through this partnership, the UBE2N–UBE2V1 complex is particularly important for immune signaling, while the UBE2N–UBE2V2 complex functions in the DNA damage response.
- In immunity, UBE2N is indispensable for the NF-κB signaling pathway. Upon activation of pattern-recognition receptors (such as Toll-like receptors, TNF receptor, or IL-1 receptor), UBE2N facilitates K63-linked ubiquitination of signaling intermediates like TRAF6. This modification acts as a scaffold to recruit and activate downstream kinases, ultimately leading to the nuclear translocation of NF-κB and transcription of pro-inflammatory genes. Similarly, UBE2N participates in the regulation of interferon responses, making it essential for antiviral defense. Dysregulation of UBE2N activity can lead to exaggerated inflammation or impaired immune defense, contributing to autoinflammatory diseases and chronic infections.
- In the context of DNA repair, UBE2N–UBE2V2 complexes are required for the cellular response to DNA double-strand breaks. By catalyzing K63-linked ubiquitin chain formation at sites of damage, UBE2N helps recruit DNA repair proteins such as BRCA1 and RAP80. This ensures accurate repair of damaged DNA and preservation of genomic stability. Cells lacking UBE2N show hypersensitivity to genotoxic stress and exhibit chromosomal instability, highlighting its role in safeguarding genome integrity.
- Clinically, UBE2N has been linked to both cancer and neurodegenerative disorders. Overexpression of UBE2N has been reported in breast, ovarian, prostate, and lung cancers, where it may enhance DNA repair and immune evasion, supporting tumor survival. Conversely, inhibition of UBE2N has been shown to sensitize tumors to DNA-damaging agents, making it a promising target for cancer therapy. In neurodegeneration, abnormal ubiquitination patterns involving UBE2N have been associated with conditions such as Parkinson’s disease and Huntington’s disease, where dysregulated protein quality control contributes to neuronal loss.
- Structurally, UBE2N contains the conserved ubiquitin-conjugating (UBC) catalytic domain, with an active cysteine residue that accepts ubiquitin from an E1 enzyme. Its functional specificity is conferred by its obligate partnership with UEV proteins, which shape the ubiquitin chain topology. This cooperative mechanism allows UBE2N to direct ubiquitination toward signaling rather than degradation, distinguishing it from many other E2 enzymes.
- In summary, UBE2N is a specialized E2 enzyme dedicated to K63-linked ubiquitination, playing essential roles in immune signaling, DNA repair, and cellular stress responses. Mutations, dysregulation, or overexpression of UBE2N can contribute to cancer, immune disorders, and neurodegenerative diseases. Because of its central role in both immunity and genome maintenance, UBE2N is an emerging therapeutic target, with inhibitors under investigation for use in cancer and inflammatory conditions.
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