Selective Hypoxia-Sensitive Oxomer Formation by FIH Prevents Binding of the NF-κB Inhibitor IκBβ to NF-κB Subunits.

Pharmacologic inhibitors of cellular hydroxylase oxygen sensors are protective in multiple preclinical models of inflammation. However, the molecular mechanisms underlying this regulation are only partly understood, preventing clinical translation. We previously proposed a new mechanism for cellular oxygen sensing: oxygen-dependent, (likely) covalent protein oligomer (oxomer) formation.

PHD1-3 oxygen sensors in vivo-lessons learned from gene deletions.

Oxygen sensors enable cells to adapt to limited oxygen availability (hypoxia), affecting various cellular and tissue responses. Prolyl-4-hydroxylase domain 1-3 (PHD1-3; also called Egln1-3, HIF-P4H 1-3, HIF-PH 1-3) proteins belong to the Fe- and 2-oxoglutarate-dependent dioxygenase superfamily and utilise molecular oxygen (O) alongside 2-oxoglutarate as co-substrate to hydroxylate two proline residues of α subunits of the dimeric hypoxia inducible factor (HIF) transcription factor. PHD1-3-mediated hydroxylation of HIF-α leads to its degradation and inactivation.

Oxomer- and Reporter Gene-Based Analysis of FIH Activity in Cells.

Cellular and tissue adaptations to oxygen deprivation (hypoxia) are necessary for both normal physiology and disease. Responses to hypoxia are initiated by the cellular oxygen sensors prolyl-4-hydroxylase domain (PHD) proteins 1-3 and factor inhibiting HIF (FIH). These enzymes regulate the transcription factor hypoxia-inducible factor (HIF) in a hypoxia-sensitive manner.

The Asparagine Hydroxylase FIH: A Unique Oxygen Sensor.

Limited oxygen availability (hypoxia) commonly occurs in a range of physiological and pathophysiological conditions, including embryonic development, physical exercise, inflammation, and ischemia. It is thus vital for cells and tissues to monitor their local oxygen availability to be able to adjust in case the oxygen supply is decreased. The cellular oxygen sensor factor inhibiting hypoxia-inducible factor (FIH) is the only known asparagine hydroxylase with hypoxia sensitivity.

The Deubiquitinase OTUB1 Is a Key Regulator of Energy Metabolism.

Dysregulated energy metabolism is a major contributor to a multitude of pathologies, including obesity and diabetes. Understanding the regulation of metabolic homeostasis is of utmost importance for the identification of therapeutic targets for the treatment of metabolically driven diseases. We previously identified the deubiquitinase OTUB1 as substrate for the cellular oxygen sensor factor-inhibiting HIF (FIH) with regulatory effects on cellular energy metabolism, but the physiological relevance of OTUB1 is unclear.