ACBD5

ACBD5 is a peroxisomal tail-anchored membrane protein that functions both as a very-long-chain fatty acyl-CoA capture factor for peroxisomal β-oxidation and as the principal tether linking peroxisomes to the endoplasmic reticulum. Its N-terminal acyl-CoA binding domain faces the cytosol and preferentially binds very-long-chain fatty acyl-CoAs, channeling them into peroxisomes for β-oxidation; loss of ACBD5 causes VLCFA accumulation, impaired myelination, and cytoskeletal deregulation in a mouse model (PMID:27899449, PMID:38066620). ACBD5 simultaneously anchors peroxisomes to the ER by engaging ER-resident VAPA/VAPB through an FFAT-like motif, an interaction dynamically tuned by GSK3β-mediated phosphorylation, thereby supporting plasmalogen synthesis, cholesterol homeostasis, and peroxisome membrane expansion (PMID:28108526, PMID:28108524, PMID:35019937). ACBD5 physically interacts with its paralog ACBD4, which modulates rather than duplicates ACBD5's tethering and metabolic functions (PMID:37414147).

1. 2014 Medium

   Identification of an ACBD5-RET fusion gene in papillary thyroid cancer revealed that the ACBD5 locus could participate in oncogenic rearrangements, though this concerned a neomorphic fusion rather than native ACBD5 function.

   Evidence RT-PCR, NIH3T3 transfection, ERK phosphorylation, and nude mouse xenograft assay

   PMID:25175022

   Open questions at the time

   • The oncogenic activity derives from constitutive RET kinase signaling, not from ACBD5 domains
   • No insight into the physiological role of wild-type ACBD5
2. 2016 High

   Establishing that ACBD5 is a peroxisomal tail-anchored protein whose cytosol-facing acyl-CoA binding domain preferentially captures VLC-CoAs for peroxisomal β-oxidation answered the long-standing question of how VLCFAs are delivered to the peroxisomal membrane.

   Evidence Subcellular fractionation, protease protection, acyl-CoA binding assays, CRISPR KO in HeLa, patient fibroblast biochemistry, domain-deletion rescue, VLCFA quantification

   PMID:27799409 PMID:27899449

   Open questions at the time

   • Whether ACBD5 hands VLC-CoAs directly to a transporter (e.g., ABCD1) or acts via another intermediary was not resolved
   • Structural basis of VLC-CoA selectivity over shorter-chain acyl-CoAs not determined
3. 2017 High

   Discovery that ACBD5 binds VAPA/VAPB via an FFAT-like motif to form the principal peroxisome–ER tether resolved how peroxisomes establish membrane contact sites with the ER and linked this tether to plasmalogen synthesis, cholesterol homeostasis, and peroxisome growth.

   Evidence Reciprocal Co-IP, BioID proximity labeling, FFAT-mutant constructs, live-cell peroxisome motility imaging, lipid analysis in ACBD5/VAP-depleted cells — replicated across two independent laboratories

   PMID:28108524 PMID:28108526

   Open questions at the time

   • The lipid transfer machinery operating at ACBD5–VAP contact sites was not identified
   • Whether the acyl-CoA binding and tethering functions are mechanistically coupled or independent was unclear
4. 2018 Medium

   Overexpression studies in hippocampal neurons revealed that ACBD5 restricts long-range microtubule-driven peroxisome transport, and a VAPB-binding-deficient mutant still altered peroxisome distribution, suggesting an additional VAPB-independent tethering or anchoring mechanism in neurons.

   Evidence Confocal live-cell imaging in primary hippocampal neurons with wild-type and FFAT-mutant ACBD5 overexpression

   PMID:30589881

   Open questions at the time

   • The molecular identity of the VAPB-independent anchoring partner was not determined
   • Only overexpression was tested; loss-of-function in neurons was not performed
   • Single-laboratory observation
5. 2022 High

   Identification of GSK3β as a kinase that phosphorylates the ACBD5 FFAT-like motif and flanking regions provided the first signaling mechanism that dynamically regulates peroxisome–ER contact site abundance.

   Evidence Phospho-proteomic MS, phosphatase treatment, site-directed mutagenesis of FFAT phosphosites, GSK3β inhibition/overexpression, proximity ligation assay quantification of contact sites

   PMID:35019937

   Open questions at the time

   • Upstream signals that activate GSK3β toward ACBD5 in physiological contexts were not defined
   • Whether phosphorylation also affects acyl-CoA binding affinity was not tested
   • Phosphatase(s) reversing the modification were not identified
6. 2023 High

   Demonstrating that ACBD5 physically interacts with its paralog ACBD4 independently of VAPB, and that ACBD4 loss increases rather than decreases VLCFA β-oxidation, clarified the non-redundant roles of the two peroxisomal ACBDs and established ACBD5 as the primary tether and metabolic factor.

   Evidence Reciprocal Co-IP, HEK293 ACBD4/ACBD5 single and double KO, lipidomics, β-oxidation flux assays

   PMID:37414147

   Open questions at the time

   • The mechanism by which ACBD4 negatively regulates β-oxidation flux is unresolved
   • Whether the ACBD5–ACBD4 interaction is stoichiometric or regulated was not addressed
7. 2024 Medium

   An Acbd5 knockout mouse recapitulated human VLCFA accumulation and revealed downstream consequences including deregulated actin dynamics, giant axonopathy, and impaired myelination — phenotypes partially rescued by AAV-mediated gene delivery, establishing in vivo causality and therapeutic potential.

   Evidence CRISPR/Cas9 Acbd5 G357* mouse, lipidomics, proteomics, neuronal VLCFA treatment with actin dynamics assay, AAV gene therapy rescue with gait and histological endpoints

   PMID:38066620

   Open questions at the time

   • The actin dynamics link was shown by exogenous VLCFA treatment of neurons rather than by direct ACBD5 reconstitution in those cells
   • Long-term efficacy and cell-type specificity of AAV rescue were not determined
   • Whether cytoskeletal defects are a direct lipotoxic effect or secondary to myelin loss is unclear

• Key unresolved questions include the identity of the lipid transfer protein(s) operating at ACBD5-mediated peroxisome–ER contact sites, the structural basis for VLC-CoA selectivity, whether the acyl-CoA binding and ER-tethering functions are mechanistically coupled, and the VAPB-independent anchoring partner in neurons.
• No lipid transfer protein at ACBD5–VAP contacts has been identified
• No high-resolution structure of ACBD5 or its complexes exists
• Coupling versus independence of the two ACBD5 functions (acyl-CoA binding and ER tethering) is untested