Yagita and Y. peroxisomal localization of ACBD5 are prerequisite for efficient VLCFA -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 -oxidation. Based on our Rabbit Polyclonal to MRPS36 findings, we propose that Catechin ACBD5 captures VLC-CoAs on the cytosolic side of the peroxisomal membrane so that the transport of VLC-CoAs into peroxisomes and subsequent -oxidation thereof can proceed efficiently. Our study reclassifies ACBD5-related phenotype as a novel peroxisomal disorder. Keywords: genetic disease, lipid metabolism, neurological disease, peroxisome, retinal degeneration, acyl-CoA-binding protein, fatty acid -oxidation, retinal dystrophy == Introduction == Peroxisomes are ubiquitous single membrane-bounded organelles that play an indispensable role in multiple metabolic pathways, including fatty acid – and -oxidation, ether lipid synthesis, docosahexaenoic acid (DHA)2synthesis, and hydrogen peroxide degradation (1). The functional significance of peroxisomes for human health is manifested by the fact that mutations in human genes encoding peroxisomal proteins lead to a spectrum of inherited peroxisomal disorders (2). Patients with peroxisomal disorders typically develop neurological abnormalities, and Catechin the clinical severity ranges from a fatal developmental disorder to a mild degenerative disorder with symptoms such as blindness, hearing impairment, and ataxia, depending on the gene responsible and the nature of the mutation (3). Peroxisomal disorders can be classified into peroxisome biogenesis disorders (PBDs) and single peroxisomal enzyme deficiencies (SEDs). PBDs, including Zellweger syndrome, are caused by defects in the formation and/or maintenance of functional peroxisomes, and consequently patients with PBDs usually lack the entire peroxisomal metabolic functions (4, 5). The vast majority of PBDs are associated with mutations inPEXgenes encoding peroxins, most of which are involved in the import of peroxisomal proteins (5, 6). Conversely, the primary defect in SEDs resides in the peroxisomal matrix enzymes or peroxisomal membrane proteins that mediate metabolite transport. Therefore , specific peroxisome-dependent metabolic pathways are affected in patients with each of the SEDs. Well known SEDs affecting peroxisomal fatty acid -oxidation pathway include X-linked adrenoleukodystrophy (X-ALD) caused by mutations in theABCD1gene (79), acyl-CoA oxidase 1 (AOx) deficiency caused by mutations in theAOxgene (10, 11), and D-bifunctional protein deficiency caused by mutations in theHSD17B4gene (12, 13). Recently, a homozygous truncating mutation in theACBD5gene encoding acyl-CoA binding domain-containing 5 (ACBD5) was reported in a family with retinal dystrophy and severe neurological involvement (Ref. 14; Online Mendelian Inheritance in Man (OMIM) number 616618). 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). Previous proteomic studies using isolated mammalian peroxisomes have identified ACBD5 as a peroxisomal protein (16, 17). Therefore , the newly described ACBD5 deficiency could be considered as a novel peroxisomal disease. 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. However , the mechanisms that link ACBD5 deficiency to such a syndromic form of retinal dystrophy remain undefined. ACBD5 was recently suggested to be involved in basal autophagic degradation of peroxisome, namely pexophagy, in mammalian cell culture (18); however , the precise function of ACBD5 is not fully defined. Because ACBD5 harbors a conserved ACBD at the N terminus, it Catechin can be anticipated that ACBD5 exerts its function(s) through binding to acyl-CoAs and that ACBD5 functions in a peroxisome-dependent lipid metabolic pathway. Here, we demonstrate that ACBD5 is a peroxisomal tail-anchored protein exposing its N-terminal ACBD to the cytosol. ACBD5 is required for achieving efficient very-long-chain fatty acid (VLCFA) -oxidation, and ACBD5 deficiency leads to accumulation of cellular phospholipids containing VLCFAs. Importantly, the N-terminal ACBD and peroxisomal localization of.