Cardio-, hepato- and pneumoprotective effects of autophagy checkpoint inhibition by targeting DBI/ACBP - Centre de recherche des Cordeliers Access content directly
Preprints, Working Papers, ... (Preprint) Year : 2022

Cardio-, hepato- and pneumoprotective effects of autophagy checkpoint inhibition by targeting DBI/ACBP

Abstract

DBI/ACBP (diazepam binding inhibitor, also known as acyl coenzyme A binding protein), acts as a paracrine inhibitor of macroautophagy/autophagy. We characterized a monoclonal antibody neutralizing mouse DBI/ACBP (a-DBI) for its cytoprotective effects on several organs (heart, liver and lung) that were damaged by surgical procedures (ligation of coronary and hepatic arteries or bile duct ligation), a variety of different toxins (acetaminophen, bleomycin, carbon tetrachloride or concanavalin A) or a methionine/choline-deficient diet (MCD). In all these models of organ damage, a-DBI prevents cell loss, inflammation and fibrosis through pathways that are blocked by pharmacological or genetic inhibition of autophagy. The hepatoprotective effects of a-DBI against MCD are mimicked by three alternative strategies to block DBI/ACBP signaling, in particular (i) induction of DBI/ACBP-specific autoantibodies, (ii) tamoxifen-inducible knockout of the Dbi gene, and (iii) a point mutation in Gabrg2 (gamma-aminobutyric acid A receptor, subunit gamma 2; Gabrg2F77I) that abolishes binding of DBI/ACBP. We conclude that a-DBI-mediated neutralization of extracellular DBI/ACBP mediates potent autophagy-dependent organ protection by on-target effects, hence unraveling a novel and potentially useful strategy for autophagy enhancement. "Autophagy checkpoint inhibition" can be achieved by targeting DBI/ACBP.
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Dates and versions

hal-04596475 , version 1 (07-06-2024)

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Omar Motiño, Flavia Lambertucci, Gerasimos Anagnostopoulos, Sijing Li, Isabelle Martins, et al.. Cardio-, hepato- and pneumoprotective effects of autophagy checkpoint inhibition by targeting DBI/ACBP. 2024. ⟨hal-04596475⟩
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