When degenerated and subsequently ubiquitinated proteins accumulate in the cytoplasm due to extensive stress, liquid-liquid phase separation occurs via multivalent interactions between these ubiquitinated proteins and p62, resulting in the formation of a large membraneless organelle called the “p62 body.” The p62 body undergoes maturation and activates the cellular stress response pathway, particularly the KEAP1–NRF2 axis.
Ultimately, the p62 body, which contains large amounts of denatured proteins, is degraded together with its client proteins in a selective autophagy-dependent manner. In other words, this dynamically transforming p62 body plays a central role in both cellular robustness (via stress response activation) and proteostasis (via clearance of denatured proteins) under stress conditions.
Importantly, it has become increasingly clear that dysregulation of p62 body formation and clearance is associated with disease states. For instance, persistent accumulation of p62 bodies has been observed in liver diseases, where they are referred to as Mallory–Denk bodies, a pathological hallmark of various hepatic disorders including Metabolic dysfunction-associated steatotic liver disease. These findings suggest that impaired phase separation dynamics and defective autophagic turnover of p62 bodies contribute to disease pathogenesis.
In this talk, I would like to introduce the stress response and autophagic degradation mechanisms regulated by various post-translational modifications of the p62 body, and discuss their pathological implications.