ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery

Chang Hwa Jung, Chang Bong Jun, Seung Hyun Ro, Young Mi Kim, Neil Michael Otto, Jing Cao, Mondira Kundu, Do Hyung Kim

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1085 Citations (Scopus)

Abstract

Autophagy, the starvation-induced degradation of bulky cytosolic components, is up-regulated in mammalian cells when nutrient supplies are limited. Although mammalian target of rapamycin (mTOR) is known as the key regulator of autophagy induction, the mechanism by which mTOR regulates autophagy has remained elusive. Here, we identify that mTOR phosphorylates a mammalian homologue of Atg13 and the mammalian Atg1 homologues ULK1 and ULK2. The mammalian Atg13 binds both ULK1 and ULK2 and mediates the interaction of the ULK proteins with FIP200. The binding of Atg13 stabilizes and activates ULK and facilitates the phosphorylation of FIP200 by ULK, whereas knockdown of Atg13 inhibits autophagosome formation. Inhibition of mTOR by rapamycin or leucine deprivation, the conditions that induce autophagy, leads to dephosphorylation of ULK1, ULK2, and Atg13 and activates ULK to phosphorylate FIP200. These findings demonstrate that the ULK-Atg13-FIP200 complexes are direct targets of mTOR and important regulators of autophagy in response to mTOR signaling.

Original languageEnglish (US)
Pages (from-to)1992-2003
Number of pages12
JournalMolecular biology of the cell
Volume20
Issue number7
DOIs
StatePublished - Apr 1 2009

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Autophagy
Sirolimus
Starvation
Leucine
Phosphorylation
Food
Proteins

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ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery. / Jung, Chang Hwa; Jun, Chang Bong; Ro, Seung Hyun; Kim, Young Mi; Otto, Neil Michael; Cao, Jing; Kundu, Mondira; Kim, Do Hyung.

In: Molecular biology of the cell, Vol. 20, No. 7, 01.04.2009, p. 1992-2003.

Research output: Contribution to journalArticle

Jung, CH, Jun, CB, Ro, SH, Kim, YM, Otto, NM, Cao, J, Kundu, M & Kim, DH 2009, 'ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery', Molecular biology of the cell, vol. 20, no. 7, pp. 1992-2003. https://doi.org/10.1091/mbc.E08-12-1249
Jung, Chang Hwa ; Jun, Chang Bong ; Ro, Seung Hyun ; Kim, Young Mi ; Otto, Neil Michael ; Cao, Jing ; Kundu, Mondira ; Kim, Do Hyung. / ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery. In: Molecular biology of the cell. 2009 ; Vol. 20, No. 7. pp. 1992-2003.
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AU - Ro, Seung Hyun

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AU - Cao, Jing

AU - Kundu, Mondira

AU - Kim, Do Hyung

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AB - Autophagy, the starvation-induced degradation of bulky cytosolic components, is up-regulated in mammalian cells when nutrient supplies are limited. Although mammalian target of rapamycin (mTOR) is known as the key regulator of autophagy induction, the mechanism by which mTOR regulates autophagy has remained elusive. Here, we identify that mTOR phosphorylates a mammalian homologue of Atg13 and the mammalian Atg1 homologues ULK1 and ULK2. The mammalian Atg13 binds both ULK1 and ULK2 and mediates the interaction of the ULK proteins with FIP200. The binding of Atg13 stabilizes and activates ULK and facilitates the phosphorylation of FIP200 by ULK, whereas knockdown of Atg13 inhibits autophagosome formation. Inhibition of mTOR by rapamycin or leucine deprivation, the conditions that induce autophagy, leads to dephosphorylation of ULK1, ULK2, and Atg13 and activates ULK to phosphorylate FIP200. These findings demonstrate that the ULK-Atg13-FIP200 complexes are direct targets of mTOR and important regulators of autophagy in response to mTOR signaling.

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