Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:6.3.2.19 (ubiquitin-protein ligase)
 799 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ubiquitin-like modifier HLA-F adjacent transcript 10 (FAT10) directly targets its substrates for proteasomal degradation by becoming covalently attached via its C-terminal diglycine motif to internal lysine residues of its substrate proteins. The conjugation machinery consists of the bispecific E1 activating enzyme Ubiquitin-like modifier activating enzyme 6 (UBA6), the likewise bispecific E2 conjugating enzyme UBA6-specific E2 enzyme 1 (USE1), and possibly E3 ligases. By mass spectrometry analysis the ubiquitin E1 activating enzyme ubiquitin-activating enzyme 1 (UBE1) was identified as putative substrate of FAT10. Here, we confirm that UBE1 and FAT10 form a stable non-reducible conjugate under overexpression as well as under endogenous conditions after induction of endogenous FAT10 expression with proinflammatory cytokines. FAT10ylation of UBE1 depends on the diglycine motif of FAT10. By specifically downregulating FAT10, UBA6 or USE1 with siRNAs, we show that UBE1 modification depends on the FAT10 conjugation pathway. Furthermore, we confirm that UBE1 does not act as a second E1 activating enzyme for FAT10 but that FAT10ylation of UBE1 leads to its proteasomal degradation, implying a putative regulatory role of FAT10 in the ubiquitin conjugation pathway.
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PMID:Conjugation of the ubiquitin activating enzyme UBE1 with the ubiquitin-like modifier FAT10 targets it for proteasomal degradation. 2576 49

In eukaryotic cells, the post-translational modification of proteins by ubiquitin or ubiquitin-like proteins (UBLs) is the most common trigger for protein degradation and is involved in the regulation of a wide range of biological processes. FAT10 (HLA-F-adjacent transcript 10), which belongs to the UBL family, is activated specifically through the UBA6-USE1 cascade and targets substrates covalently for 26S proteasomal degradation. LMO2 is a well-recognized transcriptional regulator in hematopoietic and endothelial systems; however, it is predominantly located in the cytoplasm of epithelium-derived cells. The current study revealed that LMO2 protein interacted with the E1 ubiquitin-activating enzyme UBA6 at the C-terminal ubiquitin fold domain (UFD), which mediates the recognition and recruitment of the E2-conjugating enzyme USE1. Functionally, the LMO2-UBA6 interaction disturbed the interaction between UBA6 and USE1 and led to the decline of the overall cellular FAT10ylation level as well as the FAT10ylation and degradation of a known FAT10 substrate p62. Taken together, this study revealed a novel function of LMO2 involving in the regulatory hierarchy of UBA6-USE1-FAT10ylation pathway by targeting the E1 enzyme UBA6.
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PMID:LMO2 blocks the UBA6-USE1 interaction and downstream FAT10ylation by targeting the ubiquitin fold domain of UBA6. 2756 86