Regulating cellular function in response to changing cellular conditions, such as oxygen availability, is a fine balancing act within the body that requires the input of multiple feedback mechanisms. One such mechanism is the appropriate destruction of proteins through the N-degron pathway, whereby 2-aminoethanethiol dioxygenase (ADO) adds oxygen to proteins containing an N-terminal cysteine, marking them for proteolysis.
Primary targets of ADO are RGS4, RGS5, and RGS16, proteins that act as regulators of G-protein–coupled receptor (GPCR) signalling. These proteins function as brakes on signalling pathways that control critical processes such as growth, movement, and environmental response. When oxygen is abundant, ADO activity is high, RGS proteins are degraded efficiently, and GPCR signalling proceeds. When oxygen levels decline, ADO activity drops, RGS proteins accumulate, and signalling is reduced, allowing cells to adjust to their environment.
A role for nitric oxide (NO) in the N-degron pathway has long been recognised, but the mechanism is not yet fully understood. New research from the Ratcliffe lab at Ludwig Oxford, led by Tom Keeley, demonstrates that NO can indirectly influence protein stability by affecting mitochondrial oxygen use. The researchers found that by competitively inhibiting cytochrome c oxidase, NO temporarily reduces mitochondrial oxygen consumption, increasing the oxygen available for ADO. This allows cells to fine-tune RGS protein degradation when oxygen is limited, creating a dynamic regulatory mechanism that links metabolism to signalling.
Understanding how oxygen and NO jointly control protein stability and signalling could provide insights into how cells adapt to low-oxygen conditions, and may eventually inform strategies to influence cellular behaviour in disease contexts.