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Acyl-CoA binding protein regulates nutrient-dependent autophagy

Published:October 20, 2022DOI:https://doi.org/10.1016/j.metabol.2022.155338

      Highlights

      • A novel and noncanonical mechanism of nutrient-dependent regulation of autophagy initiation by acyl-CoA binding protein (DBI).
      • DBI binds to the phosphatidylethanolamine of the phagophore membrane to prevent LC3 lipidation at phagophore.
      • AMPK phosphorylates DBI at serine-21 during nutrient starvation.
      • Serine-21 phosphorylated DBI shows reduced affinity for phosphatidylethanolamine, eventually releasing DBI from the phagophore membrane.

      Abstract

      Background

      Homeostasis of autophagy under normal conditions and nutrient stress is maintained by adaptive activation of regulatory proteins. However, the protein-lipid crosstalk that modulates the switch from suppression to activation of autophagy initiation is largely unknown.

      Results

      Here, we show that human diazepam-binding inhibitor (DBI), also known as acyl-CoA binding protein (ACBP), binds to phosphatidylethanolamine of the phagophore membrane under nutrient-rich growth conditions, leading to inhibition of LC3 lipidation and suppression of autophagy initiation. Specific residues, including the conserved tyrosine residues of DBI, interact with phosphatidylethanolamine to stabilize the later molecule in the acyl-CoA binding cavity of the protein. Under starvation, phosphorylation of serine-21 of DBI mediated by the AMP-activated protein kinase results in a drastic reduction in the affinity of the protein for phosphatidylethanolamine. The release of serine-21 phosphorylated DBI from the phagophore upon nutrient starvation restores the high LC3 lipidation flux and maturation of the phagophore to autophagosome.

      Conclusion

      DBI acts as a strategic barrier against overactivation of phagophore maturation under nutrient-rich conditions, while triggering autophagy under nutrient-deficient conditions.

      Graphical abstract

      Keywords

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