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PMID:20537536

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Citation

Koren, I, Reem, E and Kimchi, A (2010) DAP1, a novel substrate of mTOR, negatively regulates autophagy. Curr. Biol. 20:1093-8

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.

Links

PubMed Online version:10.1016/j.cub.2010.04.041

Keywords

Apoptosis Regulatory Proteins/genetics; Apoptosis Regulatory Proteins/metabolism; Autophagy; Gene Knockdown Techniques; Humans; Intracellular Signaling Peptides and Proteins/metabolism; Phosphorylation; Protein-Serine-Threonine Kinases/metabolism; TOR Serine-Threonine Kinases

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:DAP1

involved_in

GO:0034198: cellular response to amino acid starvation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:DAP1

involved_in

GO:0010507: negative regulation of autophagy

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:MTOR

involved_in

GO:0018105: peptidyl-serine phosphorylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:MTOR

part_of

GO:0031931: TORC1 complex

ECO:0000315: mutant phenotype evidence used in manual assertion

C

Seeded From UniProt

complete


See also

References

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