The discovery of how cells sense and adapt to oxygen availability

Abstract

Oxygen is ubiquitous on the Earth’s surface and essential for the survival of almost all eukaryotes. Nearly all living organisms require molecular oxygen for the metabolism of the macro-molecules to obtain energy for growth, development and reproduction. It is the subject of immense physiological, biochemical and clinical literature. In response to inadequate oxygen availability, eukaryotic body or cells undergo adaptive changes in gene expression program that either enhance oxygen delivery or promote survival in a low oxygen environment. The discovery of the mechanism by which cells sense and adapt to oxygen availability, which is awarded the 2019 Nobel Prize in Physiology or Medicine, lays the foundation for understanding how oxygen affects multiple physiological and pathological process. Hypoxia-inducible factor 1 (HIF-1) lies at the center of the hypoxia signal transduction pathway. HIF-1 was identified in a search for molecules that enhance erythropoietin (EPO) expression in anemia or hypoxia. HIF-1 is a heterodimer composed of α and β subunits, each containing basic helix-loop-helix-PAS (bHLH-PAS) domains. HIF-1β is constitutively expressed, while HIF-1α expression depends on oxygen availability and only a limited amount of protein is stabilized in the cytoplasm. Under hypoxic conditions, expressed cytosolic HIF-1α is stabilized and translocated into the nucleus to form heterodimers with HIF-1β, then binds to hypoxia response elements (HREs) to initiate transcription of target genes. More than 1000 genes have been identified to be directly transcriptionally activated by HIF-1. The proteins encoded by HIF-1 target genes are usually divided into 2 categories: one is those proteins that increase oxygen delivery like <italic>EPO</italic>, vascular endothelial growth factor (<italic>VEGF</italic>) et al<italic>, </italic>and the other is those proteins that decrease oxygen consumption like lactate dehydrogenase A (<italic>LDHA</italic>), pyruvate dehydrogenase kinase 1 (<italic>PDK1</italic>) and so on. Under normoxic conditions, prolyl hydroxylase 2 (PHD2), which serves as the sensor of cellular oxygen levels, hydroxylates the conserved proline residues in the α subunit of HIF-1. Hydroxylated HIF-1α is recognized and bound by the ubiquitin ligase von Hippel-Lindau (VHL)/Elongin B/Elongin C/Cullin-2 complex, leading to its rapid degradation by the proteasome. HIF-1α transcription activity is negatively regulated by factor inhibiting HIF-1 (FIH-1) via FIH-1-dependent asparaginyl hydroxylation using oxygen and a-ketoglutarate as substrates, which blocks the association of the coactivators CBP (CREB-binding protein) and p300. Abnormal hypoxia signal transduction contributes to the pathogenesis of many kinds of diseases like hypertension, ocular neovascularization, cancer, erythrocytosis and so on. Currently, extensive efforts are ongoing to develop drugs for clinical treatment of hypoxia-related diseases.