Understanding how regulation of membrane contacts coordinates lipid channelling at the peroxisome-ER metabolic hub

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Conceptually, the human cell can be divided into numerous separate compartments (organelles) which form part of wider networks or production lines. Each organelle has its own specific role but also interacts and coordinates with other organelles. Metabolites such as lipids can be partially processed in one organelle before being passed onto another for further processing. Cells also have to produce new, complex lipids which are used in cell membranes throughout the body and play important roles in controlling how particular membranes function. Two organelles which are critical to produce and process lipids are the endoplasmic reticulum (ER) and the peroxisome. The ER is the key lipid-producing organelle in the cell whilst peroxisomes are associated with processing of particular lipids and detoxification of toxic by-products but also play a crucial role, in collaboration with the ER, in producing lipids (called plasmalogens and polyunsaturated fatty acids). Those are critically important in the membranes of nerve cells, where the balance of membrane lipids is important in regulating neuronal firing, the transfer of signals from one nerve cell to another. Defects in these processes, caused by abnormal peroxisomes, or by the inability of the ER and peroxisomes to work together to produce the required lipids, results in severe disorders with developmental and neurological defects. We recently discovered the protein components which mediate peroxisome-ER interaction in human cells. A protein on the membrane of peroxisomes, ACBD5, binds to a protein on the ER membrane, VAPB, and this binding event brings the two organelles into close proximity, allowing exchange of lipids between the two. Removal of ACBD5 or VAPB reduces the interaction between the ER and peroxisomes, preventing correct lipid exchange and causing cellular lipid balance to be disrupted. We also recently identified patients with mutations in the ACBD5 gene who have a severe, progressive neurological disorder. We now seek to build on our previous work to further understand how peroxisome-ER interactions are regulated and how they influence lipid metabolism. We will use mammalian cells to answer questions such as how is ACBD5 and VAPB binding achieved, under what conditions is binding switched on and off and what are the systems which control how and when this happens? Understanding this will allow us to look for strategies which will enable us to modulate these interactions, potentially leading to future therapeutic approaches to restore organelle cooperation and lipid balance in pathological conditions, where organelle contacts are disrupted. This is an extremely exciting area of biology which promises to not only deliver fundamental insights into how individual organelle interaction events in cells happen but also how failure of organelles to communicate is linked to disease, including age-related disorders.