PINK1、Keap1 和 Rtnl1 调节发育过程中内质网的选择性清除。
PINK1, Keap1, and Rtnl1 regulate selective clearance of endoplasmic reticulum during development.
机构信息
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
出版信息
Cell. 2023 Sep 14;186(19):4172-4188.e18. doi: 10.1016/j.cell.2023.08.008. Epub 2023 Aug 25.
Selective clearance of organelles, including endoplasmic reticulum (ER) and mitochondria, by autophagy plays an important role in cell health. Here, we describe a developmentally programmed selective ER clearance by autophagy. We show that Parkinson's disease-associated PINK1, as well as Atl, Rtnl1, and Trp1 receptors, regulate ER clearance by autophagy. The E3 ubiquitin ligase Parkin functions downstream of PINK1 and is required for mitochondrial clearance while having the opposite function in ER clearance. By contrast, Keap1 and the E3 ubiquitin ligase Cullin3 function downstream of PINK1 to regulate ER clearance by influencing Rtnl1 and Atl. PINK1 regulates a change in Keap1 localization and Keap1-dependent ubiquitylation of the ER-phagy receptor Rtnl1 to facilitate ER clearance. Thus, PINK1 regulates the selective clearance of ER and mitochondria by influencing the balance of Keap1- and Parkin-dependent ubiquitylation of substrates that determine which organelle is removed by autophagy.
自噬对细胞器（包括内质网（ER）和线粒体）的选择性清除在细胞健康中起着重要作用。在这里，我们描述了一种通过自噬进行的发育程序性选择性 ER 清除。我们表明，帕金森病相关的 PINK1 以及 Atl、Rtnl1 和 Trp1 受体调节自噬介导的 ER 清除。E3 泛素连接酶 Parkin 作为 PINK1 的下游因子，在清除线粒体方面起作用，而在清除 ER 方面则起相反的作用。相比之下，Keap1 和 E3 泛素连接酶 Cullin3 作为 PINK1 的下游因子，通过影响 Rtnl1 和 Atl 来调节 ER 清除。PINK1 通过改变 Keap1 的定位和 Keap1 依赖性 ER 吞噬受体 Rtnl1 的泛素化来调节 ER 清除，从而促进 ER 清除。因此，PINK1 通过影响决定哪种细胞器被自噬清除的 Keap1 和 Parkin 依赖性底物泛素化平衡来调节 ER 和线粒体的选择性清除。
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