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

从概念上讲，人类细胞可以分为许多独立的隔间(细胞器)，这些隔间构成了更广泛的网络或生产线的一部分。每个细胞器都有其特定的作用，但也与其他细胞器相互作用和协调。像脂质这样的代谢物可以在一个细胞器中部分加工，然后再传递到另一个细胞器进行进一步加工。细胞还必须产生新的、复杂的脂类，这些脂类在全身细胞膜中使用，并在控制特定膜的功能方面发挥重要作用。内质网(ER)和过氧化物体是产生和处理脂质的两个关键细胞器。内质网是细胞中关键的产脂细胞器，而过氧体与特定脂类的加工和有毒副产物的解毒有关，但也与内质网合作，在产生脂类(称为血浆原和多不饱和脂肪酸)方面发挥关键作用。这些在神经细胞膜中至关重要，在神经细胞膜中，膜脂的平衡在调节神经元放电、将信号从一个神经细胞转移到另一个神经细胞方面非常重要。这些过程中的缺陷，由异常的过氧化酶体引起，或由于内质网和过氧化酶体无法协同工作来产生所需的脂质，导致严重的发育和神经缺陷。我们最近发现了在人类细胞中介导过氧化物酶-内质网相互作用的蛋白质组分。过氧化物体膜上的蛋白质ACBD5与内质网膜上的蛋白质VAPB结合，这一结合事件使两个细胞器紧密相连，允许两者之间的脂质交换。去除ACBD5或VAPB会减少ER和过氧酶体之间的相互作用，阻止正确的脂肪交换，并导致细胞脂质平衡被破坏。我们最近还发现了ACBD5基因突变的患者，他们患有严重的进行性神经疾病。我们现在寻求在我们以前工作的基础上，进一步了解过氧化物体-ER相互作用是如何调节的，以及它们是如何影响脂质代谢的。我们将使用哺乳动物细胞来回答这样的问题：ACBD5和VAPB结合是如何实现的，结合在什么条件下开启和关闭，以及控制这种结合如何发生和何时发生的系统是什么？理解这一点将使我们能够寻找策略，使我们能够调节这些相互作用，可能导致未来的治疗方法，以恢复细胞器合作和脂类平衡在病理条件下，细胞器接触被破坏。这是生物学中一个极其令人兴奋的领域，它不仅有望提供关于细胞中单个细胞器相互作用事件如何发生的基本见解，而且还将提供细胞器未能沟通与疾病，包括与年龄相关的疾病的联系。

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.