- USE1 (UBA6-specific E2 enzyme 1), also known as UBE2Z, is a specialized member of the ubiquitin-conjugating enzyme (E2) family.
- Unlike many E2 enzymes that can interact with the primary ubiquitin-activating enzyme UBA1, USE1 is unique in that it exclusively pairs with UBA6 (Ubiquitin-like modifier-activating enzyme 6). This specificity defines a distinct branch of the ubiquitination pathway, often referred to as the UBA6–USE1 axis, which regulates a restricted but important subset of proteins.
- Like other E2 enzymes, USE1 functions as a carrier in the ubiquitination cascade. After ubiquitin (or the ubiquitin-like protein FAT10) is activated by UBA6, it is transferred via a thioester bond to the active-site cysteine of USE1. USE1 then works with selected E3 ubiquitin ligases to attach ubiquitin or FAT10 to target proteins, thereby controlling their stability, function, or localization. The strict coupling between UBA6 and USE1 ensures that this pathway remains distinct from the more general UBA1-dependent system, allowing for regulation of specialized cellular processes.
- Biologically, the UBA6–USE1 system has been implicated in protein quality control, embryonic development, neuronal regulation, and immune responses. USE1 plays a critical role in FAT10 conjugation (FAT10ylation), a process linked to immune signaling, antigen presentation, and inflammation. Unlike ubiquitination, FAT10 modification generally leads to rapid proteasomal degradation of substrates, bypassing the need for polyubiquitin chains. This positions USE1 as an important player in immune system regulation and cellular stress adaptation.
- Disruption of USE1 function has been associated with human neurodevelopmental disorders. Pathogenic variants in the USE1 gene (UBE2Z) have been linked to developmental delay, intellectual disability, seizures, and autism spectrum disorder. These conditions are thought to result from impaired ubiquitin or FAT10 signaling in neurons, leading to defective protein turnover and synaptic regulation. Experimental models also suggest that USE1 deficiency can affect cell proliferation and differentiation, further emphasizing its developmental importance.
- Beyond neurology, USE1 is increasingly studied in the context of cancer and immune-related diseases. Changes in USE1 expression have been detected in certain tumors, where altered ubiquitination pathways can promote tumorigenesis by destabilizing tumor suppressors or supporting oncogenic signaling. In immunity, because of its role in FAT10 conjugation, USE1 may influence inflammatory responses, pathogen defense, and immune tolerance.
- Structurally, USE1 contains the characteristic ubiquitin-conjugating (UBC) catalytic domain with an active cysteine residue that forms a thioester bond with ubiquitin. It also has sequence features that help mediate its exclusive recognition by UBA6, preventing it from cross-reacting with UBA1. This structural specificity highlights the evolutionary separation of the UBA6–USE1 pathway from the canonical ubiquitin system.
- In summary, USE1 (UBE2Z) is a unique E2 enzyme that partners exclusively with UBA6 to regulate specialized ubiquitin and FAT10 conjugation pathways. Its activity is essential for development, neuronal function, immune signaling, and possibly cancer regulation. Dysfunction of USE1 contributes to neurodevelopmental syndromes and may play a role in tumor progression and immune dysregulation. Because of its selectivity, USE1 and the UBA6–USE1 axis are emerging as important subjects of biomedical research, with potential therapeutic implications in both neurological and immune-related diseases.
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