Ubiquitin-like modifier activating enzyme 6 (UBA6)

Ubiquitin-like modifier activating enzyme 6 (UBA6) is an atypical E1 activating enzyme with the unique property of activating both ubiquitin and the ubiquitin-like protein FAT10 for conjugation to substrate proteins[1][2][5][6]. UBA6 acts through an ATP-dependent multi-step catalytic mechanism, forming thioester-linked intermediates and facilitating downstream protein modification and degradation. In contrast to the canonical E1 enzyme UBA1, UBA6 operates at lower expression levels but is upregulated in specific cell states, such as during immune maturation or stress. UBA6 functions in distinct cellular compartments, partners with specific E2 conjugating enzymes (notably USE1), and orchestrates separate branches of ubiquitin/FAT10 signaling. It modulates key processes including protein turnover, autophagy, immune responses, and is implicated in the pathogenesis of cancer, inflammation, and rare diseases. As a drug target, its dual specificity requires precise modulation to avoid widespread disruptions in proteostasis. Research is ongoing to develop selective inhibitors and understand its role in disease[1][5][6].

Other names

UBE1L2Monocyte protein 4 (MOP4)Ubiquitin-activating enzyme E1-like protein 2E1-L2Ubiquitin-activating enzyme 6MOP-4FLJ10808Ubiquitin-activating enzyme E1-like 2

Selectively inhibiting the E1 enzymatic activity—drugs or research compounds (e.g., Compound 1) covalently modify UBA6, preventing activation of ubiquitin and/or FAT10