Abstract
The covalent attachment of the cytokine-inducible ubiquitin-like modifier HLA-F adjacent transcript 10 (FAT10) to hundreds of substrate proteins leads to their rapid degradation by the 26 S proteasome independently of ubiquitylation. Here, we identify another function of FAT10, showing that it interferes with the activation of SUMO1/2/3 in vitro and down-regulates SUMO conjugation and the SUMO-dependent formation of promyelocytic leukemia protein (PML) bodies in cells. Mechanistically, we show that FAT10 directly binds to and impedes the activity of the heterodimeric SUMO E1 activating enzyme AOS1/UBA2 by competing very efficiently with SUMO for activation and thioester formation. Nevertheless, activation of FAT10 by AOS1/UBA2 does not lead to covalent conjugation of FAT10 with substrate proteins which relies on its cognate E1 enzyme UBA6. Hence, we report that one ubiquitin-like modifier (FAT10) inhibits the conjugation and function of another ubiquitin-like modifier (SUMO) by impairing its activation.
Highlights
The covalent attachment of the cytokine-inducible ubiquitin-like modifier HLA-F adjacent transcript 10 (FAT10) to hundreds of substrate proteins leads to their rapid degradation by the 26 S proteasome independently of ubiquitylation
Our results suggest a competitive mechanism in which FAT10 itself is activated by AOS1/UBA2 but not transferred onto substrates leading to a blockage of the SmallUbiquitin-like Modifier (SUMO) conjugation pathway
While investigating JunB as a substrate of FAT10 we have uncovered a so far unknown mechanism how SUMO conjugation is regulated by FAT10
Summary
The covalent attachment of the cytokine-inducible ubiquitin-like modifier HLA-F adjacent transcript 10 (FAT10) to hundreds of substrate proteins leads to their rapid degradation by the 26 S proteasome independently of ubiquitylation We identify another function of FAT10, showing that it interferes with the activation of SUMO1/2/3 in vitro and downregulates SUMO conjugation and the SUMO-dependent formation of promyelocytic leukemia protein (PML) bodies in cells. 1234567890():,; Modification of proteins with ubiquitin (Ub) or ubiquitinlike (UBL) modifiers regulates virtually all cell biological pathways in eukaryotic cells[1] To exert their functions, UBL modifiers get covalently attached to their substrates by modifier-specific enzymatic cascades involving an E1 activating enzyme, an E2 conjugating enzyme, and an E3 ligase, which enables covalent attachment of the UBL modifier to its substrate.
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