Poster Presentation 11th International Symposium on Autophagy 2025

A phosphorylation-driven functional switch in p62 bodies coordinates autophagic clearance of ubiquitinated proteins (#121)

Satoko Komatsu-Hirota 1 , Keisuke Tabata 1 , Yu-shin Sou 2 , Soichiro Kakuta 3 , Jun-ichi Sakamaki 1 , Nozomi Shinomiya 1 , Jiachen Li 1 , Hiroyuki Kumeta 4 , Yuji Sakai 5 , Yuko Fujioka 6 , Manabu Abe 7 , Masato Koike 2 , Hideaki Morishita 8 , Nobuo Noda 6 , Masaaki Komatsu 1
  1. Department of Physiology, Juntendo University, Tokyo, Japan
  2. Department of Cell Biology and Neuroscience, Juntendo University, Tokyo, Japan
  3. Laboratory of Morphology and Image Analysis, Juntendo University, Tokyo, JAPAN
  4. Frontier Research Center for Advanced Material and Life Science, Hokkaido University, Sapporo, Japan
  5. Graduate School of Nanobioscience, Yokohama City University, Yokohama, Japan
  6. Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan
  7. Department of Animal Model Development, Niigata University, Niigata, Japan
  8. Department of Molecular Cell Biology, Kyushu University, Fukuoka, Japan

p62/SQSTM1 is a multifunctional scaffold protein that plays a pivotal role in cellular stress responses, protein turnover, and selective autophagy. It self-assembles with polyubiquitin chains to form liquid-like condensates, known as p62 bodies, which function as signaling hubs and cargos for autophagic degradation. In this study, we demonstrate that phosphorylation of Ser403 by TBK1 induces the miniaturization and gelation of p62 bodies, leading to their rapid and fragmented degradation. We also identify the PP2A phosphatase complex, including the PPP2R5A/B/E regulatory subunits, as responsible for Ser403 dephosphorylation. Phosphorylation within p62 bodies reduces their size and dynamics, thereby facilitating the autophagic clearance of ubiquitinated proteins. Furthermore, neurons differentiated from ES cells expressing a phospho-mimetic p62 mutant exhibited smaller p62 bodies, suggesting that Ser403 phosphorylation contributes to proteostasis by regulating the downsizing and gelation of p62 condensates.