Department of Physiology, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo, 113-8421, Japan.
Molecular and Integrative Biosciences Research Programme, University of Helsinki, Helsinki, 00014, Finland.
Nat Commun. 2021 Jan 4;12(1):16. doi: 10.1038/s41467-020-20185-1.
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.
自噬有助于液滴（包括 P 颗粒、Ape1 复合物和 p62/SQSTM1 体）的选择性降解，尽管选择性降解的分子机制和生理相关性尚不清楚。在本报告中，我们描述了内源性 p62 体的特性、自噬体生物发生对这些体的影响以及它们在体内周转的重要性。p62 体是含有泛素和核心自噬相关蛋白的低流动性凝胶。多个自噬体在 p62 凝胶上形成，并且自噬体定位 Atg8 蛋白与 p62 的相互作用将自噬体的形成指向 p62 凝胶。Keap1 也以依赖于 p62 结合的方式可逆地易位到 p62 凝胶上，以激活转录因子 Nrf2。缺乏 Atg8 相互作用依赖性选择性自噬的小鼠表明，p62 凝胶的周转不良会导致体内 Nrf2 过度激活。这些结果表明，p62 凝胶不是自噬的简单底物，而是自噬体形成和抗氧化应激的平台。
