Title : ATE1-mediated cell death and its role in tumour suppression
Abstract:
Regulation of cell death plays an important role for cellular adaptation to stress and associated signaling processes. Previous studies suggested that arginylation, a protein post-translational modification, catalyzed by evolutionarily conserved enzyme arginyltransferase 1 (Ate1), is involved in cellular stress responses and cell death regulation. Ate1 also plays an important role in diverse biological processes, and its dysfunction linked to embryonic lethality, cardiovascular defects, and aging-related diseases. Downregulation of Ate1, frequently observed in various cancer types, increases cellular tolerance to different stressors. In contrast, Ate1 expression is elevated under acute oxidative stress and promotes apoptosis in both yeast and mammalian cells. However, molecular mechanism of Ate1 mediated cell death remains poorly understood. Here, we investigated the role of Ate1 in stress-induced cell death in budding yeast and mammalian cells. In yeast, we found that Ate1 predominantly localizes in the cytoplasm under normal conditions but translocates to mitochondria under oxidative stress, where it becomes essential for Ate1-mediated cell death. Furthermore, Ate1-mediated cell death depends on components of mitochondrial permeability transition pore (MPTP). Moreover, knockouts of MPTP components or co-expression of the anti-apoptotic protein Bcl2xL, which prevents mitochondrial membrane permeabilization, also rescue cells from Ate1induced cell death. However, this process does not rely on mitochondrial electron transport chain activity or the reactive oxygen species (ROS) they generate. Similarly, in the mammalian system, wild-type MEF cells exhibited higher levels of cell death upon apoptotic stimulation compared with ATE1-knockout MEF cells. Further analysis revealed that Ate1 protein expression is reduced across multiple cancer types, while higher Ate1 expression correlates with increased drug sensitivity and improved patient survival. In conclusion, we identify Ate1 as a proapoptotic regulator of cell death and highlight its potential relevance in cancer therapeutics.
