CoChat
Sign Up
Cited by 85Metabolism and Genetic DisordersLipid metabolism and biosynthesisPeroxisome Proliferator-Activated Receptors

Deficiency of a Retinal Dystrophy Protein, Acyl-CoA Binding Domain-containing 5 (ACBD5), Impairs Peroxisomal β-Oxidation of Very-long-chain Fatty Acids

Open access
Yagita, Yuichi, Shinohara, Kyoko, Abe, Yuichi, Nakagawa, Keiko, Al-Owain, Mohammed, Alkuraya, Fowzan S., Fujiki, Yukio·2017·Journal of Biological Chemistry
DOI 10.1074/jbc.m116.760090PMC PMC5241743
Open this paper in CoChat — free accountOpen PDF

Abstract

Acyl-CoA binding domain-containing 5 (ACBD5) is a peroxisomal protein that carries an acyl-CoA binding domain (ACBD) at its N-terminal region. The recent identification of a mutation in the ACBD5 gene in patients with a syndromic form of retinal dystrophy highlights the physiological importance of ACBD5 in humans. However, the underlying pathogenic mechanisms and the precise function of ACBD5 remain unclear. We herein report that ACBD5 is a peroxisomal tail-anchored membrane protein exposing its ACBD to the cytosol. Using patient-derived fibroblasts and ACBD5 knock-out HeLa cells generated via genome editing, we demonstrate that ACBD5 deficiency causes a moderate but significant defect in peroxisomal β-oxidation of very-long-chain fatty acids (VLCFAs) and elevates the level of cellular phospholipids containing VLCFAs without affecting peroxisome biogenesis, including the import of membrane and matrix proteins. Both the N-terminal ACBD and peroxisomal localization of ACBD5 are prerequisite for efficient VLCFA β-oxidation in peroxisomes. Furthermore, ACBD5 preferentially binds very-long-chain fatty acyl-CoAs (VLC-CoAs). Together, these results suggest a direct role of ACBD5 in peroxisomal VLCFA β-oxidation. Based on our findings, we propose that ACBD5 captures VLC-CoAs on the cytosolic side of the peroxisomal membrane so that the transport of VLC-CoAs into peroxisomes and subsequent β-oxidation thereof can proceed efficiently. Our study reclassifies ACBD5-related phenotype as a novel peroxisomal disorder.

AI snapshot

Written from the paper’s full text.

TL;DR

ACBD5 is a peroxisomal tail-anchored membrane protein that exposes its N-terminal acyl-CoA binding domain to the cytosol and is required for efficient peroxisomal β-oxidation of very-long-chain fatty acids (VLCFAs). ACBD5 deficiency causes a moderate VLCFA β-oxidation defect and VLCFA-containing phospholipid accumulation without disrupting peroxisome biogenesis, suggesting ACBD5-related disease is a novel peroxisomal disorder.

Key findings

  • ACBD5 localizes to peroxisomes as a tail-anchored membrane protein: its N-terminal acyl-CoA binding domain faces the cytosol, while its C-terminal transmembrane region acts as the peroxisomal signal-anchor.
  • ACBD5 is dispensable for peroxisome biogenesis: ΔACBD5 fibroblasts still formed PEX14-positive peroxisomes and imported membrane and matrix proteins, including PMP70, catalase, AOx, and ADAPS.
  • ACBD5 deficiency impairs peroxisomal VLCFA β-oxidation: C24:0 β-oxidation activity in ΔACBD5 fibroblasts was reduced to about 65% of control, and ACBD5-KO HeLa cells showed significantly decreased C24:0 β-oxidation.
  • ACBD5 binds VLC-CoAs preferentially: recombinant soluble ACBD5 bound C16:0-CoA in an ACBD-dependent manner, and unlabeled C24:0-CoA competed more effectively than C16:0-CoA; both the ACBD and peroxisomal localization were required to restore efficient VLCFA β-oxidation in ACBD5-KO cells.

Methods

  • Used patient-derived human skin fibroblasts: control, ΔACBD5, ΔPEX10, ΔAOx, and ΔABCD1; also generated ACBD5-KO HeLa cells with CRISPR/Cas9 using two independent gRNAs (ACBD5-KO1 and ACBD5-KO2) and reconstituted them with HA-ACBD5 variants.
  • Assessed peroxisome biogenesis and protein localization by immunofluorescence microscopy, subcellular fractionation, alkaline extraction, and immunoblotting.
  • Measured lipid composition by LC-ESI-MS/MS, peroxisomal VLCFA β-oxidation using [14C]lignoceric acid (C24:0), and in vitro acyl-CoA binding using [14C]C16:0-CoA with unlabeled C16:0-CoA or C24:0-CoA competitors; statistics used ANOVA with Dunnett’s or Bonferroni’s tests.

Limitations

  • The paper states that the precise function of ACBD5 in peroxisomal VLCFA β-oxidation remains to be defined, that loss of ACBD5 causes only a partial reduction in β-oxidation, and that an indirect role via pexophagy remains possible.
  • The paper notes that ACBD5 binding properties need more detailed determination, that protein interactors and oligomeric status should be investigated, and that future studies should determine affected retinal cell types and retinal lipid profiles in patients or animal models.
  • Evident from the text: patient-derived fibroblast data come from a single ACBD5-deficient patient, and the ACBD5-KO work is in HeLa cells under culture conditions; the in vitro binding assays use a soluble ACBD5 fragment and selected acyl-CoAs, not the full range of VLCFA substrates.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1074/jbc.m116.760090

Cites

72 of 72 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

4 of 5 cited sources checked · 2 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    ACBD5 is a peroxisomal protein identified by previous proteomic studies of isolated mammalian peroxisomes.

    “Previous proteomic studies using isolated mammalian peroxisomes have identified ACBD5 as a peroxisomal protein (16,17).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [16] Kikuchi, 2004, Proteomic analysis of rat liver peroxisome: presence of peroxisome-specific isozyme of Lon protease, J. Biol. Chem source

      The Abstract describes proteomic analysis of isolated rat liver peroxisomes. The Results identify a putative homolog of an endozepine-related protein precursor with an acyl-CoA-binding domain, but do not name it ACBD5; they also report that only a C-terminal fragment lacking that domain appeared to localize to peroxisomes. Our copy therefore does not establish the claimed identification of ACBD5 as a peroxisomal protein. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites [17] Wiese, 2007, Proteomics characterization of mouse kidney peroxisomes by tandem mass spectrometry and protein correlation profiling, Mol. Cell. Proteomics source
  • Premisecitation

    The three siblings with ACBD5 deficiency developed white matter disease and spastic paraparesis.

    “Indeed, the three siblings with ACBD5 deficiency also developed white matter disease and spastic paraparesis (14), which are frequently observed in patients with peroxisomal disorders.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [14] Abu-Safieh, 2013, Autozygome-guided exome sequencing in retinal dystrophy patients reveals pathogenetic mutations and novel candidate disease genes, Genome Res source

      The Results section (page not specified) describes three affected siblings with an ACBD5 variant and significant white matter involvement. It does not report spastic paraparesis; the clinical features it names are cone-rod dystrophy and psychomotor delay. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
  • Findingown data

    The C-terminal TMD-containing region of ACBD5 functions as the signal-anchor sequence for peroxisomal localization.

    “Therefore, these results demonstrate that the C-terminal TMD-containing region of ACBD5 functions as the signal-anchor sequence for peroxisomal localization.”
    Quote in the paperSubstantial claim
  • Findingown data

    ACBD5 is a bona fide peroxisomal membrane protein.

    “Upon alkaline extraction, ACBD5 behaved in the same manner as PEX14, a peroxisomal membrane protein, but not AOx, a peroxisomal matrix protein (Fig. 2B), indi-cating that ACBD5 is a bona fide peroxisomal membrane protein.”
    Quote in the paperSubstantial claim
  • Findingown data

    ACBD5 is required for efficient β-oxidation of VLCFAs in peroxisomes.

    “Taken all together, our data strongly suggest that ACBD5 is required for the efficient ␤-oxidation of VLCFAs in peroxisomes.”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 1
  • May combine two claims. 12

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    ACBD5 is one of the seven members of the mammalian acyl-CoA binding domain-containing protein family characterized by an N-terminal acyl-CoA binding domain.

    “ACBD5 is one of the seven members of the mammalian acyl-CoA binding domain-containing protein (ACBP) family characterized by an N-terminal acyl-CoA binding domain (ACBD) (15).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [15] Fan, 2010, Acyl-coenzyme A binding domain containing 3 (ACBD3; PAP7; GCP60): an emerging signaling molecule, Prog. Lipid Res source

  • May combine two claims.

    Findingown data

    ACBD5 is a peroxisomal tail-anchored membrane protein that exposes its acyl-CoA binding domain to the cytosol.

    “We herein report that ACBD5 is a peroxisomal tail-anchored membrane protein exposing its ACBD to the cytosol.”
    • Also stated in: § ACBD5 Is a Peroxisomal Tail-anchored Protein Exposing Its · boosted
      “Taken together, we concluded that ACBD5 is a peroxisomal tail-anchored membrane protein and exposes its ACBD to the cytosol.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The N-terminal region of ACBD5 is exposed to the cytosol whereas the C-terminal tail faces the peroxisomal matrix.

    “These results strongly suggest that the N-terminal region of ACBD5 is exposed to the cytosol whereas the C-terminal tail is translocated and faces the peroxisomal matrix.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Neither the level of PlsEtn nor that of DHA-containing phospholipids was affected in ΔACBD5 fibroblasts.

    “Apparently, neither the level of PlsEtn nor that of DHA-containing phospholipids was affected in ⌬ACBD5 fibroblasts (Fig. 4, F and G).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Both the ACBD and peroxisomal localization of ACBD5 are essential for achieving efficient β-oxidation of VLCFAs in peroxisomes.

    “suggesting that both the ACBD and peroxisomal localization of ACBD5 are essential for achieving the efficient ␤-oxidation of VLCFAs in peroxisomes.”
    • Also stated in: § Abstract · plain
      “Both the N-terminal ACBD and peroxisomal localization of ACBD5 are prerequisite for efficient VLCFA ␤-oxidation in peroxisomes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In one ACBD5-deficient patient, the plasma C26/C22 ratio was slightly elevated, whereas phytanic acid and pristanic acid concentrations were normal.

    “Laboratory investigations on one of the three ACBD5deficient patients revealed that the plasma C26/C22 ratio was slightly elevated, whereas the concentrations of branchedchain fatty acids phytanic acid and pristanic acid were normal (Table 1)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    ACBD5 deficiency has no impact on either the biosynthesis of PlsEtn or the biosynthesis of DHA.

    “Collectively, our results suggest that ACBD5 deficiency has no impact on either the biosynthesis of PlsEtn or the biosynthesis of DHA and that ACBD5 is involved in the ␤-oxidation of VLCFAs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    ACBD5 deficiency can be categorized as a single peroxisomal enzyme deficiency with typical neurological deficits.

    “Because morphological and biochemical studies on ⌬ACBD5 fibroblasts suggested that peroxisome biogenesis is normal in the absence of ACBD5 (Fig. 3), the ACBD5 deficiency can be categorized as an SED with typical neurological deficits.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    ACBD5 deficiency causes defective peroxisomal VLCFA β-oxidation, resulting in VLCFA accumulation.

    “In summary, the present work demonstrates that ACBD5 is a peroxisomal tail-anchored protein involved in peroxisomal VLCFA ␤-oxidation via preferential binding to VLC-CoAs and that ACBD5 deficiency causes defective peroxisomal VLCFA ␤-oxidation, resulting in VLCFA accumulation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Accumulation of polyunsaturated VLCFAs seems responsible for retinal degeneration in ACBD5 deficiency because loss of ACBD5 is unlikely to affect peroxisome-dependent synthesis of DHA.

    “In the case of ACBD5 deficiency, the accumulation of polyunsaturated VLCFAs (Fig. 4, C and D) seems to be responsible for the retinal degeneration because the loss of ACBD5 is unlikely to affect the peroxisome-dependent synthesis of DHA (Fig. 4G).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    ACBD5 deficiency and its associated perturbation of peroxisomal β-oxidation of VLCFAs, especially polyunsaturated VLCFAs, may cause dysregulated fatty acid homeostasis in the retina, giving rise to severe photoreceptor degeneration.

    “Thereby, we suggest that ACBD5 deficiency and its associated perturbation of peroxisomal ␤-oxidation of VLCFAs, especially polyunsaturated VLCFAs, may cause dysregulated fatty acid homeostasis in the retina, giving rise to the severe photoreceptor degeneration.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    ACBD5 is a peroxisomal ACBP possessing a preferential affinity to VLC-CoAs.

    “Collectively, our findings suggest that ACBD5 is a peroxisomal ACBP possessing a preferential affinity to VLC-CoAs, implying that ACBD5 directly mediates peroxisomal VLCFA ␤-oxidation via its acyl-CoA binding activity.”
    • Also stated in: § Abstract · plain
      “ACBD5 preferentially binds very-long-chain fatty acyl-CoAs (VLC-CoAs).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    ACBD5 is a peroxisomal tail-anchored protein involved in peroxisomal VLCFA β-oxidation via preferential binding to VLC-CoAs.

    “In summary, the present work demonstrates that ACBD5 is a peroxisomal tail-anchored protein involved in peroxisomal VLCFA ␤-oxidation via preferential binding to VLC-CoAs and that ACBD5 deficiency causes defective peroxisomal VLCFA ␤-oxidation, resulting in VLCFA accumulation.”
    Quote in the paperSubstantial claim
13 of 13

  • The paper relies on this without support.

    Fibroblasts and HeLa cells are adequate models for peroxisomal VLCFA β-oxidation in human tissues relevant to retinal dystrophy.

    “Using patient-derived fibroblasts and ACBD5 knock-out HeLa cells generated via genome editing, we demonstrate that ACBD5 deficiency causes a moderate but significant defect in peroxisomal ␤-oxidation of very-long-chain fatty acids (VLCFAs)”

  • The paper relies on this without support.

    The C24:0 β-oxidation activity measured in fibroblasts reflects the efficiency of peroxisomal VLCFA β-oxidation in vivo.

    “we then measured the peroxisomal VLCFA ␤-oxidation activity and found that the ␤-oxidation activity toward lignoceric acid (C24:0) in ⌬ACBD5 fibroblasts was reduced to ϳ65% of control fibroblasts (Fig. 4E).”

  • The paper relies on this without support.

    VLC-PtdCho levels in fibroblasts are a valid proxy for VLCFA accumulation in affected tissues such as retina.

    “Similar to ⌬ABCD1 fibroblasts, ⌬ACBD5 fibroblasts exhibited a slight but significant elevation in the total amount of VLC-PtdCho species (Fig. 4A).”

  • The paper relies on this without support.

    The in vitro acyl-CoA binding properties of sACBD5 reflect those of full-length peroxisomal ACBD5 in cells.

    “Collectively, our findings suggest that ACBD5 is a peroxisomal ACBP possessing a preferential affinity to VLC-CoAs, implying that ACBD5 directly mediates peroxisomal VLCFA ␤-oxidation via its acyl-CoA binding activity.”
4 of 4

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Altered plasmalogen metabolism may also contribute to the tissue-specific manifestations of RDLKD.

    “In addition, altered plasmalogen metabolism may also contribute to the tissue-specific manifestations of RDLKD.”

    From The neurological pathology of peroxisomal ACBD5 deficiency – lessons from patients and mouse models (2025) · cites this paper as Yagita et al., 2017

    The Results passage on PlsEtn reports unchanged levels in ACBD5-deficient fibroblasts and concludes that ACBD5 deficiency has no apparent impact on its biosynthesis. The Discussion instead proposes accumulation of very-long-chain fatty acids as a contributor to the retinal phenotype. These fibroblast findings do not rule out every tissue-specific possibility, but the paper does not propose altered plasmalogen metabolism as a contributor. (LLM, conf=0.82)

    Checked by a reasoning model — may be wrong.

    Experimental — accuracy not yet measured

  • ACBD5 is specifically required for β-oxidation of VLCFA.

    “reinforcing the notion that ACBD5 is specifically required for β-oxidation of VLCFA”

    From The neurological pathology of peroxisomal ACBD5 deficiency – lessons from patients and mouse models (2025) · cites this paper as Yagita et al., 2017

    The Results section reports that ACBD5-deficient fibroblasts have reduced VLCFA β-oxidation while the measured PlsEtn and DHA pathways appear unaffected, supporting a relatively specific role. But C24:0 β-oxidation retained about 65% of control activity, so the paper supports ACBD5 being required for efficient VLCFA β-oxidation, not absolutely required for it (Results, Fig. 4E–G; page unavailable). (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Despite a role for ACBD5 in PO-ER contact site formation and phospholipid transfer for membrane expansion, total peroxisomal number is not affected in ACBD5-deficient cells.

    “Notably, despite a role for ACBD5 in PO-ER contact site formation and phospholipid transfer for membrane expansion, total peroxisomal number is not affected (Yagita et al., 2017).”

    From The neurological pathology of peroxisomal ACBD5 deficiency – lessons from patients and mouse models (2025) · cites this paper as Yagita et al., 2017

    In the peroxisome-biogenesis results (page unavailable), ACBD5-deficient fibroblasts retained peroxisomal structures and normal protein import. The Discussion (page unavailable) says a marked accumulation of peroxisomes in ACBD5-knockout HeLa cells is unlikely, but does not establish that total peroxisomal number is unchanged. The cited paper also does not establish the contact-site and phospholipid-transfer mechanism mentioned as background in the sentence. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • No abnormalities in phytanic acid α-oxidation were detected in ACBD5-deficient patient fibroblasts.

    “No abnormalities in phytanic acid α-oxidation were detected, reinforcing the notion that ACBD5 is specifically required for β-oxidation of VLCFA (Ferdinandusse et al., 2017; Yagita et al., 2017).”

    From The neurological pathology of peroxisomal ACBD5 deficiency – lessons from patients and mouse models (2025) · cites this paper as Yagita et al., 2017

    The Discussion (page unavailable) reports normal phytanic acid levels in the plasma of one ACBD5-deficient patient, supporting the narrower observation that no plasma abnormality was detected. It does not report a phytanic acid α-oxidation measurement in patient fibroblasts and explicitly leaves open whether ACBD5 deficiency affects cellular branched-chain fatty acid homeostasis. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Provided that peroxisome turnover is not decreased, peroxisome biogenesis appears not to be significantly reduced by a lack of ACBD5, nor is the import of peroxisomal proteins disrupted.

    “Provided that peroxisome turnover is not decreased, the biogenesis of peroxisomes appears not to be significantly reduced by a lack of ACBD5, nor is the import of peroxisomal proteins disrupted (Yagita et al., 2017).”

    From The neurological pathology of peroxisomal ACBD5 deficiency – lessons from patients and mouse models (2025) · cites this paper as Yagita et al., 2017

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • The two purportedly independent guide RNAs have identical listed sequences

    Major

    Removing the line-break hyphens from the listed oligonucleotides gives identical sequences for gRNA1 and gRNA2. This contradicts the claim that the knockout cell lines were generated with different guide RNAs, which is used to argue against off-target effects.

  • Discussion names C26:0-CoA, but the binding assay tested C24:0-CoA

    Minor

    The discussion attributes greater binding affinity to C26:0-CoA, whereas the described competition experiment used C24:0-CoA. No C26:0-CoA binding comparison is described in the provided text.

2 of 2

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Related

Authors
Yagita, Y., Shinohara, K., Abe, Y., Nakagawa, K., Al-Owain, M., Alkuraya, F. S., & Fujiki, Y.
Affiliations
  • Kyushu University (JP)
  • King Faisal Specialist Hospital & Research Centre (SA)
Corresponding author
Fujiki, Yukio
ORCID
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2017-01
Volume
292
Issue
2
Pages
691-705
ISSN
0021-9258 (ISSN-L)
DOI
10.1074/jbc.m116.760090
PMC
PMC5241743
OpenAlex
W2559176699
Cited by
85
References
72
Citations by year
2026: 5 · 2025: 7 · 2024: 6 · 2023: 6 · 2022: 12 · 2021: 6 · 2020: 13 · 2019: 11 · 2018: 11 · 2017: 8
FWCI
7.82
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (submittedVersion)
  • PubMed Central (submittedVersion)
Funders
  • Japan Society for the Promotion of Science (24247038, 25112518, 25116717, 26116007, 15K14511, 15K21743)
  • Kyushu University (Kyushu University Interdisciplinary Programs in Education and Projects in Research Development)
  • Takeda Science Foundation
  • Naito Foundation
  • Japan Foundation for Applied Enzymology
  • King Salman Center for Disability Research
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
Keywords
retinal dystrophy, peroxisomal beta-oxidation, very long chain fatty acids, peroxisomal membrane proteins, phospholipids, peroxisome biogenesis, peroxisomal disorders
MeSH terms
Protein Domains, Acyl Coenzyme A, Animals, Biological Transport, Active, Cytosol, Fatty Acids, HeLa Cells, Humans, Membrane Proteins, Oxidation-Reduction, Rabbits, Peroxisomes, Adaptor Proteins, Signal Transducing, Retinal Dystrophies

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-21.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-21.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review