Inhibition of acyl-CoA binding protein (ACBP) by means of a GABAARγ2-derived peptide

Autor: Gerasimos Anagnostopoulos, Ester Saavedra, Flavia Lambertucci, Omar Motiño, Jordan Dimitrov, David Roiz-Valle, Victor Quesada, Karla Alvarez-Valadez, Hui Chen, Allan Sauvat, Yan Rong, Uxía Nogueira-Recalde, Sijing Li, Léa Montégut, Mojgan Djavaheri-Mergny, Maria Castedo, Carlos Lopez-Otin, Maria Chiara Maiuri, Isabelle Martins, Guido Kroemer
Jazyk: angličtina
Rok vydání: 2024
Předmět:
Zdroj: Cell Death and Disease, Vol 15, Iss 4, Pp 1-11 (2024)
Druh dokumentu: article
ISSN: 2041-4889
DOI: 10.1038/s41419-024-06633-6
Popis: 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.
Databáze: Directory of Open Access Journals
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