Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Mol Cell. 2011 Aug 19;43(4):572-85. doi: 10.1016/j.molcel.2011.06.018.
Autophagy, the primary recycling pathway of cells, plays a critical role in mitochondrial quality control under normal growth conditions and in the response to cellular stress. The Hsp90-Cdc37 chaperone complex coordinately regulates the activity of select kinases to orchestrate many facets of the stress response. Although both maintain mitochondrial integrity, the relationship between Hsp90-Cdc37 and autophagy has not been well characterized. Ulk1, one of the mammalian homologs of yeast Atg1, is a serine-threonine kinase required for mitophagy. Here we show that the interaction between Ulk1 and Hsp90-Cdc37 stabilizes and activates Ulk1, which in turn is required for the phosphorylation and release of Atg13 from Ulk1, and for the recruitment of Atg13 to damaged mitochondria. Hsp90-Cdc37, Ulk1, and Atg13 phosphorylation are all required for efficient mitochondrial clearance. These findings establish a direct pathway that integrates Ulk1- and Atg13-directed mitophagy with the stress response coordinated by Hsp90 and Cdc37.
自噬是细胞的主要回收途径，在正常生长条件下和应对细胞应激时对线粒体质量控制起着至关重要的作用。Hsp90-Cdc37 伴侣复合物协调调节特定激酶的活性，以协调应激反应的许多方面。尽管两者都维持线粒体的完整性，但 Hsp90-Cdc37 和自噬之间的关系尚未得到很好的描述。Ulk1 是酵母 Atg1 的哺乳动物同源物之一，是丝氨酸/苏氨酸激酶，是线粒体自噬所必需的。在这里，我们表明 Ulk1 与 Hsp90-Cdc37 之间的相互作用稳定并激活了 Ulk1，这反过来又需要 Ulk1 对 Atg13 的磷酸化和释放，以及 Atg13 招募到受损的线粒体。Hsp90-Cdc37、Ulk1 和 Atg13 的磷酸化对于有效的线粒体清除都是必需的。这些发现建立了一个直接的途径，将 Ulk1 和 Atg13 指导的线粒体自噬与 Hsp90 和 Cdc37 协调的应激反应整合在一起。
