ROS-dependent S-palmitoylation activates cleaved and intact gasdermin D. (https://pubmed.ncbi.nlm.nih.gov/38599239/)

These scientists were curious about a protein called Gasdermin D (GSDMD) and how it works in our bodies when there is inflammation. They found out that GSDMD needs a special process called S-palmitoylation to form pores in our cells, which is important for our immune system to fight off infections. This process involves adding a molecule called palmitoyl to GSDMD, which helps it create pores in the cell membrane.

The scientists also discovered that this palmitoylation process is influenced by another process in our cells called mitochondria-generated reactive oxygen species (ROS). They found that when GSDMD is not properly cleaved, it can still undergo palmitoylation and cause a type of cell death called pyroptosis, which is a way for our body to get rid of infected cells.

The scientists identified two important proteins, ZDHHC5 and ZDHHC9, that help in adding palmitoyl to GSDMD. These proteins become more active when our immune system is activated, helping GSDMD to do its job better.

Overall, this study showed that the activation of GSDMD and the formation of pores in our cells is not just dependent on its cleavage process, but also on this special palmitoylation process. This new understanding could help scientists develop better ways to target GSDMD and treat inflammation-related diseases in the future.

Du G., Healy LB., David L., Walker C., El-Baba TJ., Lutomski CA., Goh B., Gu B., Pi X., Devant P., Fontana P., Dong Y., Ma X., Miao R., Balasubramanian A., Puthenveetil R., Banerjee A., Luo HR., Kagan JC., Oh SF., Robinson CV., Lieberman J., Wu H. ROS-dependent S-palmitoylation activates cleaved and intact gasdermin D. Nature. 2024 Apr 10. doi: 10.1038/s41586-024-07373-5.