Oxidation of Atg3 and Atg7 mediates inhibition of autophagy

Nat Commun. 2018 Jan 8;9(1):95. doi: 10.1038/s41467-017-02352-z.

Abstract

Macroautophagy (autophagy) is a crucial cellular stress response for degrading defective macromolecules and organelles, as well as providing bioenergetic intermediates during hypoxia and nutrient deprivation. Here we report a thiol-dependent process that may account for impaired autophagy during aging. This is through direct oxidation of key autophagy-related (Atg) proteins Atg3 and Atg7. When inactive Atg3 and Atg7 are protected from oxidation due to stable covalent interaction with their substrate LC3. This interaction becomes transient upon activation of Atg3 and Atg7 due to transfer of LC3 to phosphatidylethanolamine (lipidation), a process crucial for functional autophagy. However, loss in covalent-bound LC3 also sensitizes the catalytic thiols of Atg3 and Atg7 to inhibitory oxidation that prevents LC3 lipidation, observed in vitro and in mouse aorta. Here findings provide a thiol-dependent process for negatively regulating autophagy that may contribute to the process of aging, as well as therapeutic targets to regulate autophagosome maturation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / metabolism*
  • Animals
  • Aorta / cytology
  • Aorta / drug effects
  • Aorta / metabolism
  • Autophagosomes / drug effects
  • Autophagosomes / metabolism
  • Autophagy / drug effects*
  • Autophagy-Related Protein 7 / chemistry*
  • Autophagy-Related Protein 7 / metabolism
  • Autophagy-Related Proteins / chemistry*
  • Autophagy-Related Proteins / metabolism
  • HEK293 Cells
  • Humans
  • Hydrogen Peroxide / pharmacology*
  • Male
  • Mice, Inbred C57BL
  • Microtubule-Associated Proteins / chemistry*
  • Microtubule-Associated Proteins / metabolism
  • Myocytes, Smooth Muscle / cytology
  • Myocytes, Smooth Muscle / drug effects
  • Myocytes, Smooth Muscle / metabolism
  • Oxidation-Reduction
  • Phosphatidylethanolamines / chemistry
  • Phosphatidylethanolamines / metabolism
  • Primary Cell Culture
  • Rats
  • Sulfhydryl Compounds / chemistry
  • Ubiquitin-Conjugating Enzymes / chemistry*
  • Ubiquitin-Conjugating Enzymes / metabolism

Substances

  • Atg7 protein, mouse
  • Autophagy-Related Proteins
  • Map1lc3b protein, mouse
  • Microtubule-Associated Proteins
  • Phosphatidylethanolamines
  • Sulfhydryl Compounds
  • phosphatidylethanolamine
  • Hydrogen Peroxide
  • Ubiquitin-Conjugating Enzymes
  • Autophagy-Related Protein 7
  • Atg3 protein, mouse