Protein CoAlation is regulated by and integrated with growth factor signalling and the cellular antioxidant response

Coenzyme A (CoA) is an essential cellular cofactor and low molecular weight thiol (LMWT) that forms metabolically active thioesters involved in various metabolic pathways. Recently, CoA has emerged as an important antioxidant due to its covalent attachment to protein cysteine thiols in response to oxidative and metabolic stress. This modification, termed CoAlation, protects proteins from over-oxidation and can alter protein activity, subcellular localisation and conformation in eukaryotic and prokaryotic cells. However, whether protein CoAlation is implicated in cellular transformation or adaptation to oxidative stress in cancer cells is unknown. Cancer cells are known to harbour high basal reactive oxygen species (ROS) levels and to mitigate oxidative stress by deploying antioxidant enzymes and LMWTs, such as glutathione. Here we investigated whether CoAlation is a component of antioxidant responses in cancer cells. We found that protein CoAlation is detectable at basal levels and is also induced by oxidative stress in a range of cancer cell lines. Interestingly, much of this CoAlation occurs at the mitochondria. Levels of protein CoAlation can be modulated by inhibiting CoA and glutathione biosynthesis and are dependent on both cellular CoA and ROS levels. Deprivation of serum increases oxidative stress-induced protein CoAlation, indicating the requirement for growth and survival factors in antioxidant responses. In line with this, cells that are deficient in Insulin-like Growth Factor 1 (IGF-1) Receptor expression have higher ROS levels, express lower levels of antioxidant proteins, and have elevated levels of protein CoAlation. Overall, we conclude that protein CoAlation is an important arm of the antioxidant response, which is strongly integrated with and regulated by growth factor signalling and the broader antioxidant response.