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Autophagy gets a brake: DAP1, a novel mTOR substrate, is activated to suppress the autophagic process

Itay Koren1, Eran Reem, Adi Kimchi

  • 1Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.

Autophagy
|September 7, 2010
PubMed

Insights

Death-associated protein 1 (DAP1) acts as a brake on autophagy. Mammalian target of rapamycin (mTOR) controls DAP1 phosphorylation, preventing excessive autophagy during nutrient abundance and starvation.

Area of Science:

  • Cellular Biology
  • Molecular Biology

Background:

  • Autophagy is a vital cellular process regulated by numerous factors.
  • While positive regulators of autophagy are well-studied, negative regulators remain largely unknown.
  • Understanding these negative regulators is crucial for comprehending the balance of autophagic flux.

Purpose of the Study:

  • To identify and characterize novel negative regulators of autophagy.
  • To investigate the role of death-associated protein 1 (DAP1) as a suppressor of autophagy.
  • To elucidate the regulatory mechanism of DAP1 by mammalian target of rapamycin (mTOR).

Main Methods:

  • Identification of DAP1 as an autophagy suppressor.
  • Mapping of mTOR-dependent phosphorylation sites on DAP1 (Ser3 and Ser51).
  • Analysis of DAP1 phosphorylation status under nutrient-rich and starvation conditions.

Main Results:

  • DAP1 was identified as a direct substrate of mTOR and a suppressor of autophagy.
  • mTOR-mediated phosphorylation at Ser3 and Ser51 renders DAP1 inactive under nutrient-rich conditions.
  • Amino acid starvation leads to mTOR inactivation, dephosphorylation of DAP1, and subsequent suppression of autophagy.

Conclusions:

  • DAP1 acts as a crucial negative regulator, balancing autophagic activity.
  • The mTOR-DAP1 axis provides a buffering mechanism against excessive autophagy during nutrient deprivation.
  • This study introduces the "gas and brake" model for mTOR-mediated autophagy regulation.

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