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- Title
Inhibition of acyl-CoA binding protein (ACBP) by means of a GABA<sub>A</sub>Rγ2-derived peptide.
- Authors
Anagnostopoulos, Gerasimos; Saavedra, Ester; Lambertucci, Flavia; Motiño, Omar; Dimitrov, Jordan; Roiz-Valle, David; Quesada, Victor; Alvarez-Valadez, Karla; Chen, Hui; Sauvat, Allan; Rong, Yan; Nogueira-Recalde, Uxía; Li, Sijing; Montégut, Léa; Djavaheri-Mergny, Mojgan; Castedo, Maria; Lopez-Otin, Carlos; Maiuri, Maria Chiara; Martins, Isabelle; Kroemer, Guido
- Abstract
Acyl-CoA binding protein (ACBP) encoded by diazepam binding inhibitor (DBI) is an extracellular inhibitor of autophagy acting on the gamma-aminobutyric acid A receptor (GABAAR) γ2 subunit (GABAARγ2). Here, we show that lipoanabolic diets cause an upregulation of GABAARγ2 protein in liver hepatocytes but not in other major organs. ACBP/DBI inhibition by systemically injected antibodies has been demonstrated to mediate anorexigenic and organ-protective, autophagy-dependent effects. Here, we set out to develop a new strategy for developing ACBP/DBI antagonists. For this, we built a molecular model of the interaction of ACBP/DBI with peptides derived from GABAARγ2. We then validated the interaction between recombinant and native ACBP/DBI protein and a GABAARγ2-derived eicosapeptide (but not its F77I mutant) by pull down experiments or surface plasmon resonance. The GABAARγ2-derived eicosapeptide inhibited the metabolic activation of hepatocytes by recombinant ACBP/DBI protein in vitro. Moreover, the GABAARγ2-derived eicosapeptide (but not its F77I-mutated control) blocked appetite stimulation by recombinant ACBP/DBI in vivo, induced autophagy in the liver, and protected mice against the hepatotoxin concanavalin A. We conclude that peptidomimetics disrupting the interaction between ACBP/DBI and GABAARγ2 might be used as ACBP/DBI antagonists. This strategy might lead to the future development of clinically relevant small molecules of the ACBP/DBI system.
- Publication
Cell Death & Disease, 2024, Vol 15, Issue 4, p1
- ISSN
2041-4889
- Publication type
Article
- DOI
10.1038/s41419-024-06633-6