Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P62988 (Ubiquitin)
 4,326 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Nobel prize has been awarded for the discovery of ubiquitin as a transferable signal for the degradation of proteins by the 26S proteasome. While isopeptide linkage of a protein with a single ubiquitin does not serve as a degradation signal for the proteasome, poly-ubiquitylation via several different lysine residues within ubiquitin leads to efficient proteasomal degradation. Ubiquitin-like modifiers have not been shown to directly mediate proteasomal degradation except for the cytokine inducible modifier HLA-F adjacent transcript 10 (FAT10), which consists of two ubiquitin-like domains. FAT10 ends with a free diglycine motif at its C-terminus which is required for isopeptide linkage to hundreds of different substrates. In contrast to ubiquitin, a single FAT10 suffices to bind to the 26S proteasome and to efficiently mediate proteasomal degradation in a ubiquitin-independent manner. Here we review the data on ubiquitin-independent degradation by FAT10, on how FAT10 is conjugated to its substrates, how FAT10 binds to the 26S proteasome, and how the ubiquitin-like (UBL)-ubiquitin-associated (UBA) protein NUB1L accelerates FAT10 mediated proteolysis. Finally, with a glimpse on recently identified substrates, we will discuss the currently emerging knowledge about the biological functions of FAT10. This article is part of a Special Issue entitled: Ubiquitin-Proteasome System. Guest Editors: Thomas Sommer and Dieter H. Wolf.
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PMID:FAT10ylation as a signal for proteasomal degradation. 2333 71

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