Researchers led by Ludwig Oxford’s Thomas Keeley and Peter Ratcliffe reported in an August study in PNAS a previously unrecognized role of nitric oxide (NO) in cellular responses to oxygen sensing—one that involves the cysteine N-degron pathway for targeted protein degradation. This pathway helps mediate functional adaptations of cells to changing oxygen levels in the environment. It has also been shown to be a sensor of nitric oxide, though the mechanism by which that sensing occurs has been unclear. Its key component is 2-aminoethanethiol dioxygenase (ADO). The enzyme tags its target proteins—which include regulators of G-protein signaling—with oxygen, marking them for destruction. ADO activity rises when oxygen is abundant, permitting G-protein signaling, which modulates multiple cellular functions. It declines in hypoxic conditions, when a general slowdown in cellular processes is in order. Thomas, Peter and colleagues showed that NO regulates the stability of N-degron pathway substrates indirectly by regulating the availability of oxygen. It does this through the oxygen-dependent competitive inhibition of the core mitochondrial respiratory enzyme cytochrome C oxidase. This temporarily reduces mitochondrial oxygen consumption, increasing the oxygen available to ADO and allowing cells to fine-tune ADO-mediated protein degradation in hypoxic conditions. The researchers suggest that the mechanism helps link oxygen supply and mitochondrial respiration—and thus metabolism—to cellular responses to G-protein-coupled receptor activation.
Nitric oxide promotes cysteine N-degron proteolysis through control of oxygen availability
PNAS, 2025 August 19