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<p>p62/SQSTM1 self-assembles with polyubiquitin into liquid-like condensates (“p62 bodies”) that function as stress-signaling hubs and selective autophagy cargo. We show that TBK1-dependent phosphorylation at Ser403 acts as a threshold-dependent modulator of a condensate’s physical properties and promotes their rapid autophagic clearance. Phosphorylation within p62 bodies drives a transition from large, fluid droplets to compact, gel-like condensates that efficiently capture LC3-positive isolation membranes and accelerate the autophagic removal of ubiquitinated proteins. PP2A holoenzymes containing PPP2R5A/B/E, recruited via a KEAP1 bridge, counteract TBK1 by dephosphorylating Ser403. Homozygous p62S403E/S403E knock-in embryonic stem cells differentiate into post-mitotic neurons enriched in miniaturized, gel-like p62 bodies. Consistently, phosphorylation-mimetic knock-in mice show similar remodeling of p62 condensates in vivo, demonstrating that this phosphorylation-driven mechanism maintains proteostasis across scales. We propose that Ser403 phosphorylation functions as a molecular switch that couples the material state of p62 condensates to their stability and serves as a central control point for p62-mediated protein degradation.</p>

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Phosphorylation tunes p62 condensates to drive autophagic degradation of ubiquitinated proteins

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月5日

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  • Satoko Komatsu-Hirota,
  • Keisuke Tabata,
  • Yu-shin Sou,
  • Soichiro Kakuta,
  • Jun-ichi Sakamaki,
  • Hikaru Tsuchiya,
  • Jiachen Li,
  • Hiroyuki Kumeta,
  • Yuji Sakai,
  • Yuko Fujioka,
  • Daisuke Noshiro,
  • Shunsuke F Shimobayashi,
  • Tomo Kurimura,
  • Takashi Taniguchi,
  • Manabu Abe,
  • Masato Koike,
  • Hideaki Morishita,
  • Nobuo N Noda,
  • Masaaki Komatsu

摘要

p62/SQSTM1 self-assembles with polyubiquitin into liquid-like condensates (“p62 bodies”) that function as stress-signaling hubs and selective autophagy cargo. We show that TBK1-dependent phosphorylation at Ser403 acts as a threshold-dependent modulator of a condensate’s physical properties and promotes their rapid autophagic clearance. Phosphorylation within p62 bodies drives a transition from large, fluid droplets to compact, gel-like condensates that efficiently capture LC3-positive isolation membranes and accelerate the autophagic removal of ubiquitinated proteins. PP2A holoenzymes containing PPP2R5A/B/E, recruited via a KEAP1 bridge, counteract TBK1 by dephosphorylating Ser403. Homozygous p62S403E/S403E knock-in embryonic stem cells differentiate into post-mitotic neurons enriched in miniaturized, gel-like p62 bodies. Consistently, phosphorylation-mimetic knock-in mice show similar remodeling of p62 condensates in vivo, demonstrating that this phosphorylation-driven mechanism maintains proteostasis across scales. We propose that Ser403 phosphorylation functions as a molecular switch that couples the material state of p62 condensates to their stability and serves as a central control point for p62-mediated protein degradation.