Shun Kageyama1, Sigurdur Runar Gudmundsson2, Yu-Shin Sou3, Yoshinobu Ichimura1, Naoki Tamura4, Saiko Kazuno5, Takashi Ueno5, Yoshiki Miura5, Daisuke Noshiro6, Manabu Abe7, Tsunehiro Mizushima8, Nobuaki Miura9, Shujiro Okuda9, Hozumi Motohashi10, Jin-A Lee11, Kenji Sakimura7, Tomoyuki Ohe12, Nobuo N Noda6, Satoshi Waguri4, Eeva-Liisa Eskelinen13,14, Masaaki Komatsu15. 1. Department of Physiology, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo, 113-8421, Japan. 2. Molecular and Integrative Biosciences Research Programme, University of Helsinki, Helsinki, 00014, Finland. 3. Department of Cell Biology and Neuroscience, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo, 113-8421, Japan. 4. Department of Anatomy and Histology, Fukushima Medical University School of Medicine, Hikarigaoka, Fukushima, 960-1295, Japan. 5. Laboratory of Proteomics and Biomolecular Science, Research Support Center, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo, 113-8421, Japan. 6. Institute of Microbial Chemistry (BIKAKEN), Shinagawa-ku, Tokyo, 141-0021, Japan. 7. Department of Animal Model Development, Brain Research Institute, Niigata University, Niigata, 951-8510, Japan. 8. Picobiology Institute, Graduate School of Life Science, University of Hyogo, 3-2-1, Kouto, Kamigori-cho, Ako-gun, Hyogo, 678-1297, Japan. 9. Bioinformatics Laboratory, Niigata University Graduate School of Medical and Dental Sciences, Chuo-ku, Niigata, 951-8510, Japan. 10. Department of Gene Expression Regulation, Institute of Development, Aging and Cancer, Tohoku University, Sendai, 980-8575, Japan. 11. Department of Biological Sciences and Biotechnology, College of Life Sciences and Nanotechnology, Hannam University, Daejeon, 34430, Korea. 12. Department of Pharmaceutical Sciences, Faculty of Pharmacy, Keio University, Minato-ku, 105-8512, Tokyo, Japan. 13. Molecular and Integrative Biosciences Research Programme, University of Helsinki, Helsinki, 00014, Finland. eeva-liisa.eskelinen@utu.fi. 14. Institute of Biomedicine, University of Turku, Turku, FI-20014, Finland. eeva-liisa.eskelinen@utu.fi. 15. Department of Physiology, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo, 113-8421, Japan. mkomatsu@juntendo.ac.jp.
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.
Autophagy contributes to tpan class="Chemical">he selective degradation of liquid droplets, including tpan class="Chemical">he 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 thep62-gels, and the interaction of autophagosome-localizing Atg8-proteins with p62 directs autophagosome formation toward thep62-gel. Keap1 also reversibly translocates to thep62-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.
Authors: Benjamin J Ravenhill; Keith B Boyle; Natalia von Muhlinen; Cara J Ellison; Glenn R Masson; Elsje G Otten; Agnes Foeglein; Roger Williams; Felix Randow Journal: Mol Cell Date: 2019-03-07 Impact factor: 17.970
Authors: Eleonora Turco; Marie Witt; Christine Abert; Tobias Bock-Bierbaum; Ming-Yuan Su; Riccardo Trapannone; Martin Sztacho; Alberto Danieli; Xiaoshan Shi; Gabriele Zaffagnini; Annamaria Gamper; Martina Schuschnig; Dorotea Fracchiolla; Daniel Bernklau; Julia Romanov; Markus Hartl; James H Hurley; Oliver Daumke; Sascha Martens Journal: Mol Cell Date: 2019-03-07 Impact factor: 19.328
Authors: Thomas John Mercer; Yohei Ohashi; Stefan Boeing; Harold B J Jefferies; Stefano De Tito; Helen Flynn; Shirley Tremel; Wenxin Zhang; Martina Wirth; David Frith; Ambrosius P Snijders; Roger Lee Williams; Sharon A Tooze Journal: EMBO J Date: 2021-06-14 Impact factor: 14.012