Acyl coenzyme A binding protein (ACBP): An aging- and disease-relevant "autophagy checkpoint"

Abstract

Acyl coenzyme A binding protein (ACBP), also known as diazepam-binding inhibitor (DBI), is a phylogenetically ancient protein present in some eubacteria and the entire eukaryotic radiation. In several eukaryotic phyla, ACBP/DBI transcends its intracellular function in fatty acid metabolism because it can be released into the extracellular space. This ACBP/DBI secretion usually occurs in response to nutrient scarcity through an autophagy-dependent pathway. ACBP/DBI and its peptide fragments then act on a range of distinct receptors that diverge among phyla, namely metabotropic G protein-coupled receptor in yeast (and likely in the mammalian central nervous system), a histidine receptor kinase in slime molds, and ionotropic gamma-aminobutyric acid (GABA)_A receptors in mammals. Genetic or antibody-mediated inhibition of ACBP/DBI orthologs interferes with nutrient stress-induced adaptations such as sporulation or increased food intake in multiple species, as it enhances lifespan or healthspan in yeast, plant leaves, nematodes, and multiple mouse models. These lifespan and healthspan-extending effects of ACBP/DBI suppression are coupled to the induction of autophagy. Altogether, it appears that neutralization of extracellular ACBP/DBI results in "autophagy checkpoint inhibition" to unleash the anti-aging potential of autophagy. Of note, in humans, ACBP/DBI levels increase in various tissues, as well as in the plasma, in the context of aging, obesity, uncontrolled infection or cardiovascular, inflammatory, neurodegenerative, and malignant diseases.

Keywords: aging; autophagy; diazepam-binding inhibitor; endozepin; evolution; metabolism.

FIGURE 1

ACBP/DBI is the most abundantly expressed protein from a family of well‐conserved orthologs. Peptide sequence alignment reveals strong sequence similarities between the human and murine orthologs, and significant similarity with ACB1 from Saccharomyces cerevisiae (a). mRNA quantification (in average transcripts per millions, TPM) of the murine and human orthologs in different organs demonstrate that DBI/Dbi is the only ubiquitously expressed gene of the family (b) and is largely predominant in most organs of the periphery; TPM data were retrieved from consensus expression levels in www.proteinatlas.org for human genes (Uhlén et al., 2015), and average TPM by tissue from all available RNAseq samples from 8‐ 24‐week‐old wild type mice in the MGI database (Baldarelli et al., 2021), as consulted on April 12, 2023.

FIGURE 2

ACBP/DBI autophagy‐dependent secretion is conserved across phylae and targets diverse transmembrane receptors. Release of the intracellular ACBP/DBI upon autophagy induction has been demonstrated in fungal, amoebozoan, and animal species. Once in the extracellular compartment, a variety of transmembrane receptors induce different downstream molecular effects upon binding of ACBP/DBI (or its orthologs). These receptors include the GPCR receptor Ste3 in Saccharomyces cerevisiae, the receptor histidine kinase DhkA in D. discoideum, the γ2 subunit of the extracellular GABAA receptor (GABRG2), the mitochondrial membrane receptor TSPO and a putative central nervous system‐specific GPCR receptor (ODN‐GPCR). ACBP, acyl CoA binding protein; DBI, diazepam binding inhibitor; GABA_AR, gamma‐amino butyric acid receptor type A; GABRG2, GABA_AR subunit γ2; GPCR, G‐protein coupled receptor; ODN, octadecaneuropeptide; TSPO, translocator protein; TTN, triakontatetraneuropeptide.

FIGURE 3

DBI orthologs are functionally linked to nutrient stress responses and aging across phylae. Phenotypic characterization of organisms deficient for DBI orthologs reveal their impact on age‐related pathways such as nutrient sensing, response to stress, and senescence in protista, fungi, plantae, and animalia species (a). RNA sequencing data from the livers of ducks from the two distinct species (Pekin and Muscovy ducks) and their hybrids (Hinny and Mule ducks) reveal that, overfeeding a high‐carbohydrate diet employed for foie gras production, Dbi expression is increased compared to ad libitum conditions (b). Data are extracted from (Herault et al., 2019). Statistical significance was tested by two‐way ANOVA, and multiple comparison was corrected with Holm–Šídák's test in GraphPad Prism (v9.5.1 for Windows, GraphPad Software www.graphpad.com).

FIGURE 4

ACBP/DBI neutralization has systemic and organ‐specific protective effects in mice. Evidence for protective effects of ACBP/DBI neutralization has been demonstrated in murine models of obesity, organ‐specific damage (liver, heart, lung, brain), and aging, with various levels of confidence ranging from correlative clues to knockout of ACBP/DBI or knockin mutations of its downstream receptor GABRG2. Created with BioRender.com.

FIGURE 5

Daily oscillations of ACBP/DBI are increased by calorie‐ and time‐restricted feeding in mice. ACBP/DBI transcripts counts were extracted from RNA sequencing data of livers from young (<1 year old) and old (1.5–2 years old) mice, collected every 4 h for 24 h (data from (Sato et al., 2017). Mild to inexistant oscillatory patterns are visible in young (a) and old (b) mice fed ad libitum with chow diet, while clear daily oscillation occurs when mice are given a single dose of calorie‐restricted food at the time of light extinction. Cycling variable identification was tested with the Jonckheere‐Terpstra‐Kendall algorithm, implemented in R (https://www.R‐project.org/) with the the MetaCycle package (Wu et al., 2016). CR, caloric restriction; JTK, Jonckheere‐Terpstra‐Kendall; ND, normal diet.

FIGURE 6

Protein and mRNA levels of ACBP/DBI in various human diseases. ACBP/DBI levels extracted from public large‐scale transcriptomics and proteomics datasets or measured specifically in human samples are elevated in a variety of human diseases. For references, see main text. Created with BioRender.com.