Abstract
Peroxisomes (POs) and the endoplasmic reticulum (ER) cooperate in cellular lipid metabolism and form tight structural associations, which were first observed in ultrastructural studies decades ago. PO-ER associations have been suggested to impact on a diverse number of physiological processes, including lipid metabolism, phospholipid exchange, metabolite transport, signaling, and PO biogenesis. Despite their fundamental importance to cell metabolism, the mechanisms by which regions of the ER become tethered to POs are unknown, in particular in mammalian cells. Here, we identify the PO membrane protein acyl-coenzyme A-binding domain protein 5 (ACBD5) as a binding partner for the resident ER protein vesicle-associated membrane protein-associated protein B (VAPB). We show that ACBD5-VAPB interaction regulates PO-ER associations. Moreover, we demonstrate that loss of PO-ER association perturbs PO membrane expansion and increases PO movement. Our findings reveal the first molecular mechanism for establishing PO-ER associations in mammalian cells and report a new function for ACBD5 in PO-ER tethering.
Highlights
Peroxisomes (POs) are multifunctional organelles that play pivotal roles in the metabolism of lipids and reactive oxygen species and are essential for human health and development (Wanders and Waterham, 2006; Nordgren and Fransen, 2014)
We show that ACBD5–vesicle-associated membrane protein-associated protein B (VAPB) interaction regulates PO–endoplasmic reticulum (ER) associations, the loss of which perturbs PO membrane expansion and increases PO motility
A mutant ACBD5 localizing to mitochondria increased association of mitochondria with VAPB-labeled ER (Fig. S1). These findings support a role for ACBD5 and VAPB in PO–ER tethering, which we further investigated using ultrastructural and biochemical approaches
Summary
Peroxisomes (POs) are multifunctional organelles that play pivotal roles in the metabolism of lipids and reactive oxygen species and are essential for human health and development (Wanders and Waterham, 2006; Nordgren and Fransen, 2014). Results from three independent experiments identified the ER membrane protein VAPB as a candidate binding partner (Table 1 and Fig. 1 A). ACBD5–VAPB binding was confirmed by immunoprecipitation (IP) after coexpression of GFP-ACBD5 and Myc-VAPB in COS-7 cells (Fig. 1 B).
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