ABSTRACT

PINK1 and PRKN, proteins mutated in Parkinson disease, selectively amplify ubiquitin signals on damaged mitochondria for elimination via mitophagy. Because all five macroautophagy/autophagy receptors in mammals possess domains binding to ubiquitin and Atg8-family proteins, they were thought to recruit Atg8-family protein labeled phagophores from a cytosolic pool. However, our recent findings show that, in addition to Atg8-family protein binding, two of the receptors CALCOCO2 and OPTN interact with RB1CC1 and ATG9A, respectively, indicating that two different axes, CALCOCO2-RB1CC1 and OPTN-ATG9A, can initiate de novo biogenesis of autophagic membranes on ubiquitin-coated damaged mitochondria. These results explain the critical roles of the autophagy receptors CALCOCO2 and OPTN in mitochondrial degradation, and their abilities to simultaneously bind multiple autophagy core proteins propose a new function, i.e. a scaffold to build multivalent interactions for the orchestrated assembly of autophagy proteins near the ubiquitinated cargo.

Abbreviations

ATG: autophagy-related; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CRABP2: cellular retinoic acid binding protein 2; LIR: MAP1LC3/LC3-interacting region; MAP1LC3: microtubule associated protein 1 light chain 3; NBR1: NBR1 autophagy cargo receptor; OPTN: optineurin; PINK1: PTEN induced kinase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; RB1CC1/FIP200: RB1 inducible coiled-coil 1; SNIPER: specific and nongenetic IAP-dependent protein eraser; SQSTM1/p62: sequestosome 1; ULK: unc-51 like autophagy activating kinase

中文翻译：

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两个不同的轴 CALCOCO2-RB1CC1 和 OPTN-ATG9A 启动 PRKN 介导的线粒体自噬。

摘要

PINK1 和 PRKN 是在帕金森病中发生突变的蛋白质，它们选择性地放大受损线粒体上的泛素信号，以通过线粒体自噬进行消除。由于哺乳动物中的所有五种巨自噬/自噬受体都具有与泛素和 Atg8 家族蛋白结合的结构域，因此它们被认为是从细胞溶质池中招募 Atg8 家族蛋白标记的吞噬细胞。然而，我们最近的研究结果表明，除了 Atg8 家族蛋白结合外，两种受体 CALCOCO2 和 OPTN 分别与 RB1CC1 和 ATG9A 相互作用，表明两个不同的轴，CALCOCO2-RB1CC1 和 OPTN-ATG9A，可以从头启动自噬膜在泛素包被的受损线粒体上的生物发生。这些结果解释了自噬受体 CALCOCO2 和 OPTN 在线粒体降解中的关键作用，

缩写

ATG：自噬相关；CALCOCO2/NDP52：钙结合和卷曲螺旋结构域 2；CRABP2：细胞视黄酸结合蛋白2；LIR：MAP1LC3/LC3 相互作用区；MAP1LC3：微管相关蛋白1轻链3；NBR1：NBR1 自噬货物受体；OPTN：视神经磷酸酶；PINK1：PTEN 诱导激酶 1；PRKN：parkin RBR E3泛素蛋白连接酶；RB1CC1/FIP200：RB1感应线圈1；SNIPER：特异性和非遗传性 IAP 依赖性蛋白橡皮擦；SQSTM1/p62：sequestosome 1；ULK：unc-51 样自噬激活激酶