@article{663168035df445689591120e9009cb64,
title = "Differential roles for ACBD4 and ACBD5 in peroxisome–ER interactions and lipid metabolism",
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.",
keywords = "ACBD4, ACBD5, ER, VAPB, fatty acid metabolism, membrane contact sites, peroxisomes",
author = "Costello, {Joseph L.} and Janet Koster and Silva, {Beatriz S. C.} and Worthy, {Harley L.} and Schrader, {Tina A.} and Christian Hacker and Josiah Passmore and Kuypers, {Frans A.} and Waterham, {Hans R.} and Michael Schrader",
note = "Funding Information: This work was supported by grants from the Biotechnology and Biological Sciences Research Council ( BB/N01541X/1 , BB/W015420/1 to M. Schrader; BB/T002255/1 to M. Schrader and J. Costello), a UK Research and Innovation Future Leader Fellowship Award ( MR/T019409/1 to J. Costello), a Royal Society Research Grant Award ( RGS∖R2∖192378 to J. Costello), European Union{\textquoteright}s Horizon 2020 research and innovation program under the Marie Sk{\l}odowska-Curie grant agreement No 812968 PERICO (to M. Schrader, H. Waterham). MRC CiC 08135 , University of Exeter (to M. S.). For the purpose of open access, the author has applied a Creative Commons Attribution (CC BY) licence to any Author Accepted Manuscript version arising. Funding Information: We thank all lab members for stimulating discussions and comments on the manuscript and Eric Soupene for providing in-vitro lipid binding data. We thank all colleagues who provided reagents (see Tables) and P. Cherek, P. Mooijer and C. van Roermund for technical assistance. J. L. C. J. K. B. S. C. S. H. L. W. T. A. S. C. H. and J. P. investigation; J. L. C. J. K. B. S. C. S. H. L. W. T. A. S. C. H. and J. P. formal analysis; J. L. C. M. S. H. R. W. and F. A. K. conceptualization; J. L. C. M. S. H. R. W. and F. A. K. writing–reviewing and editing; J. L. C. M. S. H. R. W. and F. A. K. supervision; J. L. C. M. S. H. R. W. and F. A. K. project administration; J. L. C. M. S., H. R. W. and F. A. K. funding acquisition; J. L. C. Writing–original draft. This work was supported by grants from the Biotechnology and Biological Sciences Research Council (BB/N01541X/1, BB/W015420/1 to M. Schrader; BB/T002255/1 to M. Schrader and J. Costello), a UK Research and Innovation Future Leader Fellowship Award (MR/T019409/1 to J. Costello), a Royal Society Research Grant Award (RGS∖R2∖192378 to J. Costello), European Union's Horizon 2020 research and innovation program under the Marie Sk{\l}odowska-Curie grant agreement No 812968 PERICO (to M. Schrader, H. Waterham). MRC CiC 08135, University of Exeter (to M. S.). For the purpose of open access, the author has applied a Creative Commons Attribution (CC BY) licence to any Author Accepted Manuscript version arising. Publisher Copyright: {\textcopyright} 2023 The Authors",
year = "2023",
month = aug,
day = "1",
doi = "https://doi.org/10.1016/j.jbc.2023.105013",
language = "English",
volume = "299",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "8",
}