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Cited by 18Lipid metabolism and biosynthesisCellular transport and secretionCancer, Lipids, and Metabolism

Differential roles for ACBD4 and ACBD5 in peroxisome-ER interactions and lipid metabolism.

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Costello, Joseph L., Koster, Janet, Silva, Beatriz S.C., Worthy, Harley L., Schrader, Tina A., Hacker, Christian, Passmore, Josiah, Kuypers, Frans A. +2 more·2023·Journal of Biological Chemistry
DOI 10.1016/j.jbc.2023.105013PMC PMC10410513
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Abstract

Peroxisomes and the endoplasmic reticulum (ER) are intimately linked subcellular organelles, physically connected at membrane contact sites. While collaborating in lipid metabolism, for example, of very long-chain fatty acids (VLCFAs) and plasmalogens, the ER also plays a role in peroxisome biogenesis. Recent work identified tethering complexes on the ER and peroxisome membranes that connect the organelles. These include membrane contacts formed via interactions between the ER protein VAPB (vesicle-associated membrane protein-associated protein B) and the peroxisomal proteins ACBD4 and ACBD5 (acyl-coenzyme A-binding domain protein). Loss of ACBD5 has been shown to cause a significant reduction in peroxisome-ER contacts and accumulation of VLCFAs. However, the role of ACBD4 and the relative contribution these two proteins make to contact site formation and recruitment of VLCFAs to peroxisomes remain unclear. Here, we address these questions using a combination of molecular cell biology, biochemical, and lipidomics analyses following loss of ACBD4 or ACBD5 in HEK293 cells. We show that the tethering function of ACBD5 is not absolutely required for efficient peroxisomal β-oxidation of VLCFAs. We demonstrate that loss of ACBD4 does not reduce peroxisome-ER connections or result in the accumulation of VLCFAs. Instead, the loss of ACBD4 resulted in an increase in the rate of β-oxidation of VLCFAs. Finally, we observe an interaction between ACBD5 and ACBD4, independent of VAPB binding. Overall, our findings suggest that ACBD5 may act as a primary tether and VLCFA recruitment factor, whereas ACBD4 may have regulatory functions in peroxisomal lipid metabolism at the peroxisome-ER interface.

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  • The presence of other PO-ER tether proteins such as ACBD4 may partially compensate in peroxisome biogenesis in ACBD5 deficiency.

    “The presence of other PO-ER tether proteins such as ACBD4 may partially compensate in peroxisome biogenesis (Costello et al., 2023).”

    From The neurological pathology of peroxisomal ACBD5 deficiency – lessons from patients and mouse models (2025) · cites this paper as Costello et al., 2023

    The Results (page unavailable) show that overexpressed ACBD4 restored peroxisome–ER contacts in ACBD5-knockout cells, and the Discussion says ACBD4 can compensate for loss of ACBD5 in tethering. The paper links these contacts to peroxisome biogenesis, but does not show that ACBD4 compensates for biogenesis itself. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • The coiled-coil domain of ACBD5 mediates homo-oligomerization and hetero-oligomerization with ACBD4.

    “Its coiled-coil domain mediates homo-oligomerization, but also hetero-oligomerization with ACBD4 (Costello et al., 2023), suggesting a more complex role at the peroxisomal membrane.”

    From The neurological pathology of peroxisomal ACBD5 deficiency – lessons from patients and mouse models (2025) · cites this paper as Costello et al., 2023

  • ACBD4 appears to differ functionally from ACBD5 and may have regulatory functions in peroxisomal lipid metabolism.

    “However, ACBD4 also appears to differ functionally from ACBD5 and may have regulatory functions in peroxisomal lipid metabolism (Costello et al., 2023).”

    From The neurological pathology of peroxisomal ACBD5 deficiency – lessons from patients and mouse models (2025) · cites this paper as Costello et al., 2023

  • ACBD5 may have a more complex role at the peroxisomal membrane.

    “Its coiled-coil domain mediates homo-oligomerization, but also hetero-oligomerization with ACBD4 (Costello et al., 2023), suggesting a more complex role at the peroxisomal membrane.”

    From The neurological pathology of peroxisomal ACBD5 deficiency – lessons from patients and mouse models (2025) · cites this paper as Costello et al., 2023

  • ACBD4 expression can compensate for the loss of ACBD5 in peroxisome-ER tethering and VLCFA β-oxidation in cell culture.

    “As ACBD4 expression can compensate for the loss of ACBD5 in peroxisome-ER tethering and VLCFA β-oxidation in cell culture (Costello et al., 2023), pharmacological upregulation of ACBD4 expression may be an approach to overcome loss of ACBD5.”

    From The neurological pathology of peroxisomal ACBD5 deficiency – lessons from patients and mouse models (2025) · cites this paper as Costello et al., 2023

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Research works printed but not linked: 42

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Authors
Costello, J. L., Koster, J., Silva, B. S. C., Worthy, H. L., Schrader, T. A., Hacker, C., Passmore, J., Kuypers, F. A., Waterham, H. R., & Schrader, M.
Affiliations
  • University of Exeter (GB)
  • Amsterdam UMC Location University of Amsterdam (NL)
  • University of Luxembourg (LU)
  • Utrecht University (NL)
  • University of California, San Francisco (US)
Corresponding author
  • Costello, Joseph L.
  • Waterham, Hans R.
  • Schrader, Michael
ORCID
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2023-08
Volume
299
Issue
8
Pages
105013
ISSN
0021-9258 (ISSN-L)
DOI
10.1016/j.jbc.2023.105013
PMC
PMC10410513
OpenAlex
W4383105849
Cited by
18
References
49
Citations by year
2026: 7 · 2025: 8 · 2024: 2 · 2023: 1
FWCI
1.81
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Open Research Exeter (University of Exeter) (acceptedVersion, cc-by)
  • Figshare (submittedVersion, cc-by)
  • Pure Amsterdam UMC (submittedVersion, cc-by)
Funders
  • MRC
  • Biotechnology and Biological Sciences Research Council (BB/N01541X/1, BB/T002255/1, BB/W015420/1)
  • Royal Society (RGS∖R2∖192378)
  • University of Exeter
  • Horizon 2020 Framework Programme
  • Horizon 2020
  • UKRI (MR/T019409/1)
  • H2020 Marie Skłodowska-Curie Actions (812968)
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
membrane contact sites, VAPB, peroxisome biogenesis, very long chain fatty acids, peroxisomal beta-oxidation, plasmalogens, lipid metabolism, tethering complexes, protein-protein interaction
MeSH terms
Carrier Proteins, Endoplasmic Reticulum, Humans, Membrane Proteins, Peroxisomes, Adaptor Proteins, Signal Transducing, Lipid Metabolism, Mitochondrial Membranes, HEK293 Cells

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