Ubiquitin carboxyl-terminal hydrolase 43 (USP43)

Ubiquitin carboxyl-terminal hydrolase 43 (USP43) is a member of the ubiquitin-specific protease family of deubiquitinating enzymes. It recognizes and hydrolyzes peptide bonds at the C-terminal glycine of ubiquitin, thereby generating monoubiquitin from polyubiquitin chains and processing ubiquitinated substrates. USP43 plays a key role in regulating the hypoxic response by associating with hypoxia-inducible factor 1-alpha (HIF-1α), facilitating its nuclear accumulation and the expression of HIF-1 target genes in a hypoxia- and phosphorylation-dependent manner. Mechanistically, USP43 associates with 14-3-3 proteins to support HIF-1α signaling, and while its enzymatic function as a DUB contributes, some non-catalytic functions are also observed. Additionally, USP43 is implicated in metastasis, where it is upregulated in a Ca_v2.2/calcium–NFAT2 axis, promoting invadopodia formation, extracellular matrix degradation, and tumor cell invasion through stabilization of cortactin in breast cancer. While no therapeutics directly targeting USP43 are currently described, its roles in hypoxia signaling and cancer metastasis make it a molecule of interest for future therapeutic development.

Other names

Ubiquitin-specific-processing protease 43ubiquitin specific peptidase 43deubiquitinating enzyme 43FLJ30626ubiquitin thioesterase 43ubiquitin thiolesterase 43

Deubiquitination of substrate proteins, Regulation of nuclear accumulation and chromatin association of HIF-1α (not solely dependent on enzymatic deubiquitination activity but also on protein–protein interactions with 14-3-3 proteins)