{Reference Type}: Journal Article
{Title}: Deubiquitinating enzyme mutagenesis screens identify a USP43-dependent HIF-1 transcriptional response.
{Author}: Pauzaite T;Wit N;Seear RV;Nathan JA;
{Journal}: EMBO J
{Volume}: 43
{Issue}: 17
{Year}: 2024 Sep 15
{Factor}: 14.012
{DOI}: 10.1038/s44318-024-00166-6
{Abstract}: The ubiquitination and proteasome-mediated degradation of Hypoxia Inducible Factors (HIFs) is central to metazoan oxygen-sensing, but the involvement of deubiquitinating enzymes (DUBs) in HIF signalling is less clear. Here, using a bespoke DUBs sgRNA library we conduct CRISPR/Cas9 mutagenesis screens to determine how DUBs are involved in HIF signalling. Alongside defining DUBs involved in HIF activation or suppression, we identify USP43 as a DUB required for efficient activation of a HIF response. USP43 is hypoxia regulated and selectively associates with the HIF-1α isoform, and while USP43 does not alter HIF-1α stability, it facilitates HIF-1 nuclear accumulation and binding to its target genes. Mechanistically, USP43 associates with 14-3-3 proteins in a hypoxia and phosphorylation dependent manner to increase the nuclear pool of HIF-1. Together, our results highlight the multifunctionality of DUBs, illustrating that they can provide important signalling functions alongside their catalytic roles.