p62/SQSTM1-droplet serves as a platform for autophagosome formation and anti-oxidative stress response

Shun Kageyama, Sigurdur Runar Gudmundsson, Yu-Shin Sou, Yoshinobu Ichimura, Naoki Tamura, Saiko Kazuno, Takashi Ueno, Yoshiki Miura, Daisuke Noshiro, Manabu Abe, Tsunehiro Mizushima, Nobuaki Miura, Shujiro Okuda, Hozumi Motohashi, Jin-A Lee, Kenji Sakimura, Tomoyuki Ohe, Nobuo N. Noda, Satoshi Waguri, Eeva-Liisa Eskelinen () and Masaaki Komatsu ()
Additional contact information
Shun Kageyama: Juntendo University Graduate School of Medicine
Sigurdur Runar Gudmundsson: University of Helsinki
Yu-Shin Sou: Juntendo University Graduate School of Medicine
Yoshinobu Ichimura: Juntendo University Graduate School of Medicine
Naoki Tamura: Fukushima Medical University School of Medicine
Saiko Kazuno: Juntendo University Graduate School of Medicine
Takashi Ueno: Juntendo University Graduate School of Medicine
Yoshiki Miura: Juntendo University Graduate School of Medicine
Daisuke Noshiro: Institute of Microbial Chemistry (BIKAKEN)
Manabu Abe: Niigata University
Tsunehiro Mizushima: University of Hyogo, 3-2-1, Kouto, Kamigori-cho
Nobuaki Miura: Niigata University Graduate School of Medical and Dental Sciences
Shujiro Okuda: Niigata University Graduate School of Medical and Dental Sciences
Hozumi Motohashi: Tohoku University
Jin-A Lee: Hannam University
Kenji Sakimura: Niigata University
Tomoyuki Ohe: Keio University
Nobuo N. Noda: Institute of Microbial Chemistry (BIKAKEN)
Satoshi Waguri: Fukushima Medical University School of Medicine
Eeva-Liisa Eskelinen: University of Helsinki
Masaaki Komatsu: Juntendo University Graduate School of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: Abstract Autophagy contributes to the selective degradation of liquid droplets, including the P-Granule, Ape1-complex and p62/SQSTM1-body, although the molecular mechanisms and physiological relevance of selective degradation remain unclear. In this report, we describe the properties of endogenous p62-bodies, the effect of autophagosome biogenesis on these bodies, and the in vivo significance of their turnover. p62-bodies are low-liquidity gels containing ubiquitin and core autophagy-related proteins. Multiple autophagosomes form on the p62-gels, and the interaction of autophagosome-localizing Atg8-proteins with p62 directs autophagosome formation toward the p62-gel. Keap1 also reversibly translocates to the p62-gels in a p62-binding dependent fashion to activate the transcription factor Nrf2. Mice deficient for Atg8-interaction-dependent selective autophagy show that impaired turnover of p62-gels leads to Nrf2 hyperactivation in vivo. These results indicate that p62-gels are not simple substrates for autophagy but serve as platforms for both autophagosome formation and anti-oxidative stress.

Date: 2021
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DOI: 10.1038/s41467-020-20185-1

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