TY - JOUR
T1 - Autophagy gets a brake
T2 - DAP1, a novel mTOR substrate, is activated to suppress the autophagic process
AU - Koren, Itay
AU - Reem, Eran
AU - Kimchi, Adi
PY - 2010/11/16
Y1 - 2010/11/16
N2 - Autophagy, a highly regulated catabolic process, is controlled by the action of positive and negative regulators. While many of the positive mediators of autophagy have been identified, very little is known about negative regulators that might counterbalance the process. We recently identified death-associated protein 1 (DAP1) as a suppressor of autophagy and as a novel direct substrate of mammalian target of rapamycin (mTOR). We found that DAP1 is functionally silent in cells growing under rich nutrient supplies through mTOR-dependent inhibitory phosphorylation on two sites, which were mapped to Ser3 and Ser51. During amino acid starvation, mTOR activity is turned off resulting in a rapid reduction in the phosphorylation of DAP1. This caused the conversion of the protein into a suppressor of autophagy, thus providing a buffering mechanism that counterbalances the autophagic flux and prevents its overactivation under conditions of nutrient deprivation. Based on these studies we propose the "gas and brake" concept in which mTOR, the main sensor that regulates autophagy in response to amino acid deprivation, also controls the activity of a specific balancing brake to prevent the overactivation of autophagy.
AB - Autophagy, a highly regulated catabolic process, is controlled by the action of positive and negative regulators. While many of the positive mediators of autophagy have been identified, very little is known about negative regulators that might counterbalance the process. We recently identified death-associated protein 1 (DAP1) as a suppressor of autophagy and as a novel direct substrate of mammalian target of rapamycin (mTOR). We found that DAP1 is functionally silent in cells growing under rich nutrient supplies through mTOR-dependent inhibitory phosphorylation on two sites, which were mapped to Ser3 and Ser51. During amino acid starvation, mTOR activity is turned off resulting in a rapid reduction in the phosphorylation of DAP1. This caused the conversion of the protein into a suppressor of autophagy, thus providing a buffering mechanism that counterbalances the autophagic flux and prevents its overactivation under conditions of nutrient deprivation. Based on these studies we propose the "gas and brake" concept in which mTOR, the main sensor that regulates autophagy in response to amino acid deprivation, also controls the activity of a specific balancing brake to prevent the overactivation of autophagy.
KW - Amino acid starvation
KW - Autophagy
KW - DAP1
KW - Phosphorylation
KW - mTOR
UR - http://www.scopus.com/inward/record.url?scp=78649266505&partnerID=8YFLogxK
U2 - 10.4161/auto.6.8.13338
DO - 10.4161/auto.6.8.13338
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AN - SCOPUS:78649266505
SN - 1554-8627
VL - 6
SP - 1179
EP - 1180
JO - Autophagy
JF - Autophagy
IS - 8
ER -