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
Graphical Abstract
Keywords
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Article info
Publication history
Published online: October 20, 2022
Accepted:
October 17,
2022
Received:
August 25,
2022
Publication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2022 Elsevier Inc. All rights reserved.
