Department of Molecular and Cellular Biology, College of Biological Sciences, University of California, Davis, CA 95616.
Department of Molecular and Cellular Biology, College of Biological Sciences, University of California, Davis, CA 95616
Proc Natl Acad Sci U S A. 2014 Jul 22;111(29):10586-91. doi: 10.1073/pnas.1406305111. Epub 2014 Jul 7.
The highly conserved Target of Rapamycin (TOR) kinase is a central regulator of cell growth and metabolism in response to nutrient availability. TOR functions in two structurally and functionally distinct complexes, TOR Complex 1 (TORC1) and TOR Complex 2 (TORC2). Through TORC1, TOR negatively regulates autophagy, a conserved process that functions in quality control and cellular homeostasis and, in this capacity, is part of an adaptive nutrient deprivation response. Here we demonstrate that during amino acid starvation TOR also operates independently as a positive regulator of autophagy through the conserved TORC2 and its downstream target protein kinase, Ypk1. Under these conditions, TORC2-Ypk1 signaling negatively regulates the Ca(2+)/calmodulin-dependent phosphatase, calcineurin, to enable the activation of the amino acid-sensing eIF2α kinase, Gcn2, and to promote autophagy. Our work reveals that the TORC2 pathway regulates autophagy in an opposing manner to TORC1 to provide a tunable response to cellular metabolic status.
雷帕霉素靶蛋白（TOR）激酶高度保守，是细胞生长和代谢对营养物质可用性的反应的中央调节剂。TOR 在两个结构和功能上不同的复合物中发挥作用，即 TOR 复合物 1（TORC1）和 TOR 复合物 2（TORC2）。通过 TORC1，TOR 负调控自噬，这是一种在质量控制和细胞动态平衡中起作用的保守过程，并且在这种能力上是适应营养剥夺反应的一部分。在这里，我们证明在氨基酸饥饿期间，TOR 还通过保守的 TORC2 及其下游靶蛋白激酶 Ypk1 独立地作为自噬的正调节剂发挥作用。在这些条件下，TORC2-Ypk1 信号转导负调节钙调神经磷酸酶，以激活氨基酸感应的 eIF2α 激酶 Gcn2，并促进自噬。我们的工作表明，TORC2 途径以与 TORC1 相反的方式调节自噬，以提供对细胞代谢状态的可调响应。
