Differential roles for ACBD4 and ACBD5 in peroxisome-ER interactions and lipid metabolism
Costello, JL; Koster, J; Silva, BSC; et al.Worthy, HL; Schrader, TA; Hacker, C; Passmore, J; Kuypers, FA; Waterham, HR; Schrader, M
Date: 4 July 2023
Article
Journal
Journal of Biological Chemistry
Publisher
Elsevier / American Society for Biochemistry and Molecular Biology
Publisher DOI
Abstract
Peroxisomes and the endoplasmic reticulum (ER) are intimately linked subcellular organelles,
physically connected at membrane contact sites. As well as collaborating in lipid metabolism,
e.g. of very long chain fatty acids (VLCFAs) and plasmalogens, the ER also plays a role in
peroxisome biogenesis. Recent work has identified tethering ...
Peroxisomes and the endoplasmic reticulum (ER) are intimately linked subcellular organelles,
physically connected at membrane contact sites. As well as collaborating in lipid metabolism,
e.g. of very long chain fatty acids (VLCFAs) and plasmalogens, the ER also plays a role in
peroxisome biogenesis. Recent work has identified tethering complexes on the ER and
peroxisome membranes which connect the organelles. These include membrane contacts
formed via interactions between the ER protein VAPB (vesicle-associated membrane proteinassociated protein B) and the peroxisomal proteins ACBD4 and ACBD5 (acyl-coenzyme Abinding 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 remains 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 accumulation of
VLCFAs. Instead, the loss of ACBD4 resulted in an increase in the rate of β-oxidation of VLCFAs.
Finally, we observe 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.
Biosciences
Faculty of Health and Life Sciences
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