Kamber Roarke A, Shoemaker Christopher J, Denic Vladimir
Northwest Labs, Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA.
Northwest Labs, Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA.
Mol Cell. 2015 Aug 6;59(3):372-81. doi: 10.1016/j.molcel.2015.06.009. Epub 2015 Jul 9.
Selective autophagy eliminates protein aggregates, damaged organelles, and other targets that otherwise accumulate and cause disease. Autophagy receptors mediate selectivity by connecting targets to the autophagosome membrane. It has remained unknown whether receptors perform additional functions. Here, we show that in yeast certain receptor-bound targets activate Atg1, the kinase that controls autophagosome formation. Specifically, we found that in nutrient-rich conditions, Atg1 is active only in a multisubunit complex comprising constitutive protein aggregates, their autophagy receptor, and a scaffold protein, Atg11. Development of a cell-free assay for Atg1-mediated phosphorylation enabled us to activate Atg1 with purified receptor-bound aggregates and Atg11. Another target, damaged peroxisomes, also activated Atg1 using Atg11 with a distinct receptor. Our work reveals that receptor-target complexes activate Atg1 to drive formation of selective autophagosomes. This regulatory logic is a key similarity between selective autophagy and bulk autophagy, which is initiated by a distinct Atg1 activation mechanism during starvation.
选择性自噬可清除蛋白质聚集体、受损细胞器及其他否则会积累并导致疾病的靶标。自噬受体通过将靶标连接至自噬体膜来介导选择性。受体是否执行其他功能尚不清楚。在此，我们表明在酵母中，某些与受体结合的靶标会激活Atg1，即控制自噬体形成的激酶。具体而言，我们发现，在营养丰富的条件下，Atg1仅在包含组成型蛋白质聚集体、其自噬受体和支架蛋白Atg11的多亚基复合物中具有活性。开发用于Atg1介导的磷酸化的无细胞检测方法使我们能够用纯化的与受体结合的聚集体和Atg11激活Atg1。另一个靶标，受损的过氧化物酶体，也使用具有不同受体的Atg11激活了Atg1。我们的工作揭示了受体-靶标复合物激活Atg1以驱动选择性自噬体的形成。这种调节逻辑是选择性自噬和整体自噬之间的关键相似之处，整体自噬在饥饿期间由不同的Atg1激活机制启动。
