Abstract
Programmed cell death is an essential mechanism to eliminate irreparably damaged cells, and requires strict regulation via signaling molecules. Recently, it has been revealed that various types of stress induce diverse forms of programmed cell death, including apoptosis, ferroptosis, and parthanatos, depending on the situation. “Parthanatos” is defined as a novel type of programmed cell death dependent on the activation of PARP-1, a signaling molecule involved in stress responses during cellular injury induced by various types of stress, such as oxidative stress, and has recently attracted much attention due to its close association with various diseases, such as neurodegenerative disorders and cancer. However, the regulatory mechanisms of parthanatos are still unknown in detail. In this study, we found that parthanatos depends on the formation and fluidity (stiffness) of ALIS (aggresome-like induced structures) triggered by the multifunctional protein p62. ALIS are droplet-like structures formed by LLPS (liquid-liquid phase separation) and probably serve as signaling hubs. p62 recognizes the ubiquitinated proteins indicating intracellular damage, and is also found to function as a sensor to various types of stress, including oxidative stress, through the oxidative modification of cysteine residues in its molecule. Moreover, we recently found that poly ADP-ribosylation by PARP-1 and phosphorylation of p62 enhance the ALIS formation and parthanatos, indicating that parthanatos is tightly regulated by the balance of several post-translational modifications. These results in our research provide a novel insight into the pathological roles of parthanatos.
