LMO2 blocks the UBA6-USE1 interaction and downstream FAT10ylation by targeting the ubiquitin fold domain of UBA6.

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.