Inhibition of acyl-CoA binding protein (ACBP) by means of a GABA A Rγ2-derived peptide

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 (GABA R) γ2 subunit (GABA Rγ2). Here, we show that lipoanabolic diets cause an upregulation of GABA Rγ2 protein in liver hepatocytes...

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Published in:Cell death & disease 2024-04, Vol.15 (4), p.249
Main 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
Format: Article
Language:English
Subjects:
Animals
Diazepam Binding Inhibitor - pharmacology
gamma-Aminobutyric Acid
Mice
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Summary: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 (GABA R) γ2 subunit (GABA Rγ2). Here, we show that lipoanabolic diets cause an upregulation of GABA Rγ2 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 GABA Rγ2. We then validated the interaction between recombinant and native ACBP/DBI protein and a GABA Rγ2-derived eicosapeptide (but not its F77I mutant) by pull down experiments or surface plasmon resonance. The GABA Rγ2-derived eicosapeptide inhibited the metabolic activation of hepatocytes by recombinant ACBP/DBI protein in vitro. Moreover, the GABA Rγ2-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 GABA Rγ2 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.
ISSN:2041-4889