The enzymes of the ubiquitylation pathway play a pivotal role in a number of cellular processes including regulated and targeted proteosomal degradation of substrate proteins. Three classes of enzymes are involved in the process of ubiquitylation; activating enzymes (E1s), conjugating enzymes (E2s) and protein ligases (E3s). UBA6 is a member of the E1 activating enzyme family and the human gene was first described by Jin et al. (2007). UBA6 shares 42% homology with UBE1 and contains all the structural elements required for E1 enzyme activity (Groettrup et al., 2008). UBA6 interacts with a number of E2 and E3 enzymes and has been shown to be involved with p53 ubiquitylation in vitro (Groettrup et al., 2008; Pelzer et al., 2007). UBA6 activates ubiquitin and the ubiquitin-like protein human leukocyte antigen F-Associated Transcript 10 (FAT10), both of which may serve as a signal for proteasomal degradation. FAT10, is encoded by the major histocompatibility (MHC) class I locus, and its expression is induced by tumor necrosis factor alpha (TNFα) and interferon-gamma (IFNγ). FAT10 expression is significantly upregulated in hepatocellular carcinoma as well as in gastrointestinal and gynecological cancers (Lee et al., 2003), however its precise biochemical and cellular functions have yet to be determined. Although FAT10 forms covalent conjugates with cellular proteins through its C-terminal diglycine motif (Raasi et al., 2001), substrates remain to be identified. Knockdown of UBA6 results in decreased FAT10 conjugation, indicating that UBA6 is required to activate FAT10 and facilitate its conjugation (Chiu et al., 2007).
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