DAP1, a novel substrate of mTOR, negatively regulates autophagy
- PMID: 20537536
- DOI: 10.1016/j.cub.2010.04.041
DAP1, a novel substrate of mTOR, negatively regulates autophagy
Abstract
Autophagy, a catabolic process responsible for the degradation of cytosolic components, is upregulated when nutrient supplies are limited. A critical step in autophagy induction comprises the inactivation of a key negative regulator of the process, the Ser/Thr kinase mammalian target of rapamycin (mTOR). Thus far, only a few substrates of mTOR that control autophagy have been identified, including ULK1 and Atg13, both of which function as positive mediators. Here we identify death-associated protein 1 (DAP1) as a novel substrate of mTOR that negatively regulates autophagy. The link of DAP1 to autophagy was first apparent in that its knockdown enhanced autophagic flux and in that it displayed a rapid decline in its phosphorylation in response to amino acid starvation. Mapping of the phosphorylation sites and analysis of phosphorylation mutants indicated that DAP1 is functionally silenced in growing cells through mTOR-dependent phosphorylations on Ser3 and Ser51. Inactivation of mTOR during starvation caused a rapid reduction in these phosphorylation sites and converted the protein into an active suppressor of autophagy. These results are consistent with a "Gas and Brake" model in which mTOR inhibition also controls a buffering mechanism that counterbalances the autophagic flux and prevents its overactivation under nutrient deprivation.
Copyright 2010 Elsevier Ltd. All rights reserved.
Similar articles
-
Autophagy gets a brake: DAP1, a novel mTOR substrate, is activated to suppress the autophagic process.Autophagy. 2010 Nov;6(8):1179-80. doi: 10.4161/auto.6.8.13338. Autophagy. 2010. PMID: 20818178 Free PMC article.
-
AMPK-independent induction of autophagy by cytosolic Ca2+ increase.Cell Signal. 2010 Jun;22(6):914-25. doi: 10.1016/j.cellsig.2010.01.015. Epub 2010 Jan 28. Cell Signal. 2010. PMID: 20114074
-
ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery.Mol Biol Cell. 2009 Apr;20(7):1992-2003. doi: 10.1091/mbc.e08-12-1249. Epub 2009 Feb 18. Mol Biol Cell. 2009. PMID: 19225151 Free PMC article.
-
Role of an intrinsically disordered conformation in AMPK-mediated phosphorylation of ULK1 and regulation of autophagy.Mol Biosyst. 2012 Jan;8(1):91-6. doi: 10.1039/c1mb05265a. Epub 2011 Aug 18. Mol Biosyst. 2012. PMID: 21853163 Review.
-
mTOR regulation of autophagy.FEBS Lett. 2010 Apr 2;584(7):1287-95. doi: 10.1016/j.febslet.2010.01.017. Epub 2010 Jan 18. FEBS Lett. 2010. PMID: 20083114 Free PMC article. Review.
Cited by
-
Induction of Autophagy by Extract from Corydalis heterocarpa for Skin Anti-Aging.Mar Drugs. 2024 Mar 8;22(3):127. doi: 10.3390/md22030127. Mar Drugs. 2024. PMID: 38535468 Free PMC article.
-
Death-associated protein 3 in cancer-discrepant roles of DAP3 in tumours and molecular mechanisms.Front Oncol. 2024 Jan 30;13:1323751. doi: 10.3389/fonc.2023.1323751. eCollection 2023. Front Oncol. 2024. PMID: 38352299 Free PMC article. Review.
-
DAP1 regulates osteoblast autophagy via the ATG16L1-LC3 axis in Graves' disease-induced osteoporosis.J Orthop Surg Res. 2023 Sep 21;18(1):711. doi: 10.1186/s13018-023-04171-z. J Orthop Surg Res. 2023. PMID: 37735431 Free PMC article.
-
Role of CELF2 in ferroptosis: Potential targets for cancer therapy (Review).Int J Mol Med. 2023 Oct;52(4):88. doi: 10.3892/ijmm.2023.5291. Epub 2023 Aug 18. Int J Mol Med. 2023. PMID: 37594127 Free PMC article. Review.
-
mTOR Signaling Pathway and Gut Microbiota in Various Disorders: Mechanisms and Potential Drugs in Pharmacotherapy.Int J Mol Sci. 2023 Jul 22;24(14):11811. doi: 10.3390/ijms241411811. Int J Mol Sci. 2023. PMID: 37511569 Free PMC article. Review.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Molecular Biology Databases
Research Materials
Miscellaneous