Inhibition of acyl-CoA binding protein (ACBP) by means of a GABAARγ2-derived peptide - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue (Data Paper) Cell Death and Disease Année : 2024

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

Ester Saavedra
  • Fonction : Auteur
Omar Motiño
Jordan Dimitrov
David Roiz-Valle
  • Fonction : Auteur
Victor Quesada
  • Fonction : Auteur
Uxía Nogueira-Recalde
  • Fonction : Auteur
Carlos Lopez-Otin
  • Fonction : Auteur
Isabelle Martins

Résumé

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 (GABA A R) γ2 subunit (GABA A Rγ2). Here, we show that lipoanabolic diets cause an upregulation of GABA A 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 A Rγ2. We then validated the interaction between recombinant and native ACBP/DBI protein and a GABA A Rγ2-derived eicosapeptide (but not its F77I mutant) by pull down experiments or surface plasmon resonance. The GABA A Rγ2-derived eicosapeptide inhibited the metabolic activation of hepatocytes by recombinant ACBP/DBI protein in vitro. Moreover, the GABA A 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 A 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.
Fichier principal
Vignette du fichier
10998878.pdf (4.15 Mo) Télécharger le fichier
Origine Fichiers éditeurs autorisés sur une archive ouverte

Dates et versions

hal-04596741 , version 1 (31-05-2024)

Identifiants

Citer

Gerasimos Anagnostopoulos, Ester Saavedra, Flavia Lambertucci, Omar Motiño, Jordan Dimitrov, et al.. Inhibition of acyl-CoA binding protein (ACBP) by means of a GABAARγ2-derived peptide. Cell Death and Disease, 2024, 15 (4), pp.249. ⟨10.1038/s41419-024-06633-6⟩. ⟨hal-04596741⟩
4 Consultations
0 Téléchargements

Altmetric

Partager

Gmail Mastodon Facebook X LinkedIn More