Cited by 12Lipid metabolism and biosynthesisCellular transport and secretionCancer, Lipids, and Metabolism

New insights into the functions of ACBD4/5-like proteins using a combined phylogenetic and experimental approach across model organisms.

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Kors, Suzan, Schuster, Martin, Maddison, Daniel C., Kilaru, Sreedhar, Schrader, Tina A., Costello, Joseph L., Islinger, Markus, Smith, Gaynor A. +1 more·2024·Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Abstract

Acyl-CoA binding domain-containing proteins (ACBDs) perform diverse but often uncharacterised functions linked to cellular lipid metabolism. Human ACBD4 and ACBD5 are closely related peroxisomal membrane proteins, involved in tethering of peroxisomes to the ER and capturing fatty acids for peroxisomal β-oxidation. ACBD5 deficiency causes neurological abnormalities including ataxia and white matter disease. Peroxisome-ER contacts depend on an ACBD4/5-FFAT motif, which interacts with ER-resident VAP proteins. As ACBD4/5-like proteins are present in most fungi and all animals, we combined phylogenetic analyses with experimental approaches to improve understanding of their evolution and functions. Notably, all vertebrates exhibit gene sequences for both ACBD4 and ACBD5, while invertebrates and fungi possess only a single ACBD4/5-like protein. Our analyses revealed alterations in domain structure and FFAT sequences, which help understanding functional diversification of ACBD4/5-like proteins. We show that the Drosophila melanogaster ACBD4/5-like protein possesses a functional FFAT motif to tether peroxisomes to the ER via Dm_Vap33. Depletion of Dm_Acbd4/5 caused peroxisome redistribution in wing neurons and reduced life expectancy. In contrast, the ACBD4/5-like protein of the filamentous fungus Ustilago maydis lacks a FFAT motif and does not interact with Um_Vap33. Loss of Um_Acbd4/5 resulted in an accumulation of peroxisomes and early endosomes at the hyphal tip. Moreover, lipid droplet numbers increased, and mitochondrial membrane potential declined, implying altered lipid homeostasis. Our findings reveal differences between tethering and metabolic functions of ACBD4/5-like proteins across evolution, improving our understanding of ACBD4/5 function in health and disease. The need for a unifying nomenclature for ACBD proteins is discussed.

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Crossref · 10.1016/j.bbamcr.2024.119843

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  • Knockout of ACBD5 in HeLa and other mammalian cells did not affect pexophagy.

    “knockout of ACBD5 in HeLa and other mammalian cells did not affect pexophagy (Ferdinandusse et al., 2017; Kors et al., 2024).”

    From The neurological pathology of peroxisomal ACBD5 deficiency – lessons from patients and mouse models (2025) · cites this paper as Kors et al., 2024

    Section 2.6 (p. 9) reports that other studies did not find ACBD5 involved in peroxisome degradation, and Section 3.2 (p. 13) says human ACBD5 does not appear to affect it. The cited paper does not specify ACBD5 knockout in HeLa or other mammalian cells; its own mammalian-cell experiment tested overexpression in H9C2 myoblasts. (LLM, conf=0.84)

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Research works printed but not linked: 2

  1. [85][85] L.N. Townsend, H. Clarke, D. Maddison, K.M. Jones, L. Amadio, A. Jefferson, U. Chughtai, D.M. Bis, S. Züchner, N.D. Allen, W. Van der Goes, O.M. van Naters, G.A. Smith Peters, Cdk12 maintains the integrity of adult axons by suppressing actin remodeling, Cell Death Dis. 9 (2023) 1 -12, https://doi.org/10.1038/ s41420-023-01642-4. -
  2. [96][96] S.C. Guimar ˜ aes, S. Kilaru, M. Schrader, M. Schuster, Labeling of peroxisomes for live cell imaging in the filamentous fungus Ustilago maydis , Methods Mol. Biol. 1595 (2017) 131 -150, https://doi.org/10.1007/978-1-4939-6937-1\_13. - · DOI

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Authors
Kors, S., Schuster, M., Maddison, D. C., Kilaru, S., Schrader, T. A., Costello, J. L., Islinger, M., Smith, G. A., & Schrader, M.
Affiliations
  • University of Exeter (GB)
  • Cardiff University (GB)
  • Heidelberg University (DE)
Corresponding author
Schrader, Michael
Venue
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research
Publisher
Elsevier BV
Published
2024-12
Volume
1871
Issue
8
Pages
119843
ISSN
0167-4889 (ISSN-L)
OpenAlex
W4402450038
Cited by
12
References
110
Citations by year
2026: 4 · 2025: 8
FWCI
1.93
Type
journal article
Language
en
Open access
Locations
  • Biochimica et Biophysica Acta (BBA) - Molecular Cell Research (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
  • Figshare (submittedVersion, cc-by)
  • Open Research Exeter (University of Exeter) (submittedVersion, cc-by)
  • Apollo (University of Cambridge) (submittedVersion, cc-by)
Funders
  • Biotechnology and Biological Sciences Research Council (BB/T002255/1, BB/W015420/1, BB/N01541X/1)
  • German Center for Cardiovascular Disease (81X2500211)
  • UK Research and Innovation Medical Research Council (MC_PC_16030/1)
  • German Research Foundation (397476530)
  • UK Research and Innovation (MR/T019409/1)
  • The Royal Society (RGS\\R2\\192378)
  • Leverhulme Trust (RPG-2020-369)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
Keywords
FFAT motif, VAP proteins, peroxisomal beta-oxidation, peroxisome biogenesis, lipid metabolism, Drosophila melanogaster, Ustilago maydis, lipid droplets, mitochondrial membrane potential, evolutionary conservation, protein domain structure, nomenclature
MeSH terms
Animals, Basidiomycota, Drosophila melanogaster, Endoplasmic Reticulum, Female, Humans, Male, Membrane Proteins, Phylogeny, Peroxisomes, Diazepam Binding Inhibitor, Drosophila Proteins, Adaptor Proteins, Signal Transducing, Lipid Metabolism

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