title: Deficiency of a Retinal Dystrophy Protein, Acyl-CoA Binding Domain-containing 5 (ACBD5), Impairs Peroxisomal β-Oxidation of Very-long-chain Fatty Acids.
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.
authors.affiliation: From the Department of Biology and Graduate School of Systems Life Sciences, Kyushu University, 744 Motooka Nishi-ku, Fukuoka 819-0395, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Yagita
authors.affiliation: From the Department of Biology and Graduate School of Systems Life Sciences, Kyushu University, 744 Motooka Nishi-ku, Fukuoka 819-0395, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Shinohara
authors.affiliation: the Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan, and.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Abe
authors.affiliation: From the Department of Biology and Graduate School of Systems Life Sciences, Kyushu University, 744 Motooka Nishi-ku, Fukuoka 819-0395, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Nakagawa
authors.affiliation: the King Faisal Specialist Hospital and Research Center, MBC-03 P. O. Box 3354, Riyadh 11211, Saudi Arabia.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Al-Owain
authors.affiliation: the King Faisal Specialist Hospital and Research Center, MBC-03 P. O. Box 3354, Riyadh 11211, Saudi Arabia.
authors.forename: Fowzan S
authors.initials: FS
authors.lastname: Alkuraya
authors.affiliation: the Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan, and yfujiki@kyudai.jp.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Fujiki
mesh_terms: D000214:Acyl Coenzyme A / Q000235:genetics / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001693:Biological Transport, Active / Q000235:genetics; D003600:Cytosol / Q000378:metabolism*; D005227:Fatty Acids / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D020675:Peroxisomes / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000072417:Protein Domains; D011817:Rabbits; D058499:Retinal Dystrophies / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: C548478:ACBD5 protein, human; D000214:Acyl Coenzyme A; D048868:Adaptor Proteins, Signal Transducing; D005227:Fatty Acids; D008565:Membrane Proteins
keywords: acyl-CoA-binding protein; fatty acid β-oxidation; genetic disease; lipid metabolism; neurological disease; peroxisome; retinal degeneration; retinal dystrophy