A research team led by Wu Qiao at the School of Life Sciences, Xiamen University, has identified myosin heavy chain 9 (MYH9) as an execution protein in cuproptosis, a form of copper-dependent cell death. The study, titled "Copper ion-induced MYH9 polymerization executes cuproptosis", was published online in Cell. The team also identified HThPA, the first non-copper ionophore compound shown to trigger cuproptosis by releasing copper from intracellular stores.
The researchers used two parallel screening strategies to identify proteins that sense copper ions inside cells. Their findings showed that copper ions directly bind to MYH9 and induce its polymerization, with the extent of polymerization increasing with copper levels. Deleting the MYH9 gene inhibited cuproptosis, while MYH9 polymerization occurred before cell death in both time- and dose-dependent experiments.
Using optogenetic techniques, the team further demonstrated that inducing MYH9 polymerization could trigger the full cuproptosis phenotype even in the absence of copper ions, establishing polymerization as a sufficient condition for the process. The study also found that MYH9 polymerization strengthens its interaction with actin, disrupting the assembly of G-actin into F-actin and leading to cytoskeletal breakdown.
The researchers found that DLAT, released from mitochondria following membrane rupture, acetylates MYH9, reducing its surface electrostatic potential and facilitating copper binding.
Screening 1,163 small molecules identified HThPA, which activates the Nur77-PDK1-CHAC1 pathway to degrade glutathione and release intracellular copper. In mouse models of drug-resistant liver and gastric cancers, HThPA showed stronger antitumor effects and less systemic toxicity than copper ionophore-based treatment, offering a potential strategy for overcoming tumor drug resistance.
