- Ubiquitin D (UBD), more widely recognized as FAT10, is a member of the ubiquitin-like modifier (UBL) family, characterized by its structural resemblance to ubiquitin but distinct biological functions.
- Unlike ubiquitin, which is universally conserved in eukaryotes, UBD is found only in mammals. The protein consists of two ubiquitin-like domains in tandem, connected by a short flexible linker, and carries a conserved diglycine (GG) motif at its C-terminus. This motif is essential for its conjugation to substrate proteins through a process termed FAT10ylation, which, although analogous to ubiquitination, is mechanistically unique.
- The conjugation machinery involves the dedicated E1-activating enzyme UBA6 and the specific E2-conjugating enzyme USE1, differentiating UBD from canonical ubiquitin pathways.
- UBD expression is tightly regulated at the transcriptional level and is strongly inducible under immune and inflammatory conditions. Proinflammatory cytokines, particularly tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ), are potent inducers of UBD transcription through NF-κB and STAT1 signaling. Under normal physiological conditions, UBD is expressed at low levels in certain immune-related organs such as the thymus, spleen, and lymph nodes. However, during infection, immune activation, or inflammation, its levels rise sharply. This inducible nature underscores its role as an effector of immune regulation and cellular stress responses.
- Functionally, UBD plays a central role in protein quality control, immune defense, and cell cycle regulation. Conjugation of UBD to target proteins generally leads to their rapid degradation via the 26S proteasome. Unlike ubiquitin, UBD does not require polymeric chain formation; a single UBD tag is sufficient to target substrates for destruction. This makes UBD a powerful regulator of transient signaling events that demand quick protein turnover. Its activity has been linked to antigen presentation through MHC class I molecules, regulation of apoptosis, and control of mitotic progression. Furthermore, UBD itself is inherently unstable and degraded together with its substrates, ensuring a tight and short-lived regulatory effect.
- Pathologically, UBD overexpression has been reported in a variety of cancers, including hepatocellular carcinoma, colorectal carcinoma, gastric cancer, and pancreatic cancer. In these contexts, it has been associated with enhanced tumor cell proliferation, migration, chromosomal instability, and poor clinical prognosis. Beyond oncology, UBD is implicated in chronic inflammatory diseases, autoimmune disorders, and infectious pathologies where immune signaling is dysregulated. Its dual nature—as both a mediator of protective immune responses and a contributor to pathological processes—makes UBD an important molecule in immunology and cancer biology.
- Because of its inducibility, selective expression in immune-related tissues, and unique mode of action, UBD is increasingly regarded as a potential biomarker for inflammation and cancer progression, as well as a possible therapeutic target. Ongoing research continues to unravel its mechanistic roles in cellular signaling networks, offering insights into how this ubiquitin-like protein bridges immunity, protein homeostasis, and disease.
