Pauzaite Tekle, Nathan James A
Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Jeffrey Cheah, Biomedical Centre, Department of Medicine, University of Cambridge, Cambridge CB2 0AW, U.K.
Biochem Soc Trans. 2024 Dec 19;52(6):2253-2265. doi: 10.1042/BST20230861.
Hypoxia Inducible transcription Factors (HIFs) are central to the metazoan oxygen-sensing response. Under low oxygen conditions (hypoxia), HIFs are stabilised and govern an adaptive transcriptional programme to cope with prolonged oxygen starvation. However, when oxygen is present, HIFs are continuously degraded by the proteasome in a process involving prolyl hydroxylation and subsequent ubiquitination by the Von Hippel Lindau (VHL) E3 ligase. The essential nature of VHL in the HIF response is well established but the role of other enzymes involved in ubiquitination is less clear. Deubiquitinating enzymes (DUBs) counteract ubiquitination and provide an important regulatory aspect to many signalling pathways involving ubiquitination. In this review, we look at the complex network of ubiquitination and deubiquitination in controlling HIF signalling in normal and low oxygen tensions. We discuss the relative importance of DUBs in opposing VHL, and explore roles of DUBs more broadly in hypoxia, in both VHL and HIF independent contexts. We also consider the catalytic and non-catalytic roles of DUBs, and elaborate on the potential benefits and challenges of inhibiting these enzymes for therapeutic use.
缺氧诱导转录因子(HIFs)是后生动物氧感应反应的核心。在低氧条件下(缺氧),HIFs会被稳定下来,并调控一个适应性转录程序以应对长期的氧饥饿。然而,当有氧气存在时,HIFs会在一个涉及脯氨酰羟化以及随后被冯·希佩尔-林道(VHL)E3连接酶泛素化的过程中被蛋白酶体持续降解。VHL在HIF反应中的重要性质已得到充分证实,但参与泛素化的其他酶的作用尚不清楚。去泛素化酶(DUBs)会抵消泛素化作用,并为许多涉及泛素化的信号通路提供重要的调控方面。在这篇综述中,我们探讨了在正常氧张力和低氧张力下,泛素化和去泛素化在控制HIF信号传导中的复杂网络。我们讨论了DUBs在对抗VHL方面的相对重要性,并更广泛地探讨了DUBs在缺氧情况下在VHL和HIF独立背景下的作用。我们还考虑了DUBs的催化和非催化作用,并详细阐述了抑制这些酶用于治疗的潜在益处和挑战。