Deubiquitinating enzyme mutagenesis screens identify a USP43-dependent HIF-1 transcriptional response.
EMBO J
; 43(17): 3677-3709, 2024 Sep.
Article
em En
| MEDLINE
| ID: mdl-39009674
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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Subunidade alfa do Fator 1 Induzível por Hipóxia
/
Enzimas Desubiquitinantes
Limite:
Humans
Idioma:
En
Revista:
EMBO J
Ano de publicação:
2024
Tipo de documento:
Article