Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 111, Issue 29, Pages 10586-10591Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1406305111
Keywords
Atg8; Gcn4
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Funding
- National Institutes of Health (NIH) [GM086387, R01GM062942, R01GM097432]
- T-32 Training Grant in Molecular and Cellular Biology
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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 Ca2+/calmodulin-dependent phosphatase, calcineurin, to enable the activation of the amino acid-sensing eIF2 alpha 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.
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