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室（细胞器），这些隔室形成更广泛的网络或生产线的一部分。每个细胞器都有自己特定的作用，但也与其他细胞器相互作用和协调。代谢产物如脂质可以在一个细胞器中部分加工，然后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、复杂的脂质，这些脂质用于整个身体的细胞膜，并在控制特定膜的功能方面发挥重要作用。两种对产生和加工脂质至关重要的细胞器是内质网（ER）和过氧化物酶体。ER是细胞中关键的脂质产生细胞器，而过氧化物酶体与特定脂质的加工和有毒副产物的解毒有关，但与ER合作，在产生脂质（称为缩醛磷脂和多不饱和脂肪酸）中也起着至关重要的作用。这些在神经细胞膜中至关重要，其中膜脂质的平衡对于调节神经元放电，即信号从一个神经细胞转移到另一个神经细胞至关重要。这些过程中的缺陷，由异常过氧化物酶体引起，或由ER和过氧化物酶体不能一起工作以产生所需的脂质引起，导致具有发育和神经缺陷的严重疾病。我们最近发现了在人类细胞中介导过氧化物酶体-ER相互作用的蛋白质组分。过氧化物酶体膜上的蛋白质ACBD 5与ER膜上的蛋白质VAPB结合，这种结合事件使两个细胞器紧密靠近，允许两者之间的脂质交换。ACBD 5或VAPB的去除减少了ER和过氧化物酶体之间的相互作用，阻止了正确的脂质交换，并导致细胞脂质平衡被破坏。我们最近还发现了ACBD 5基因突变的患者，他们患有严重的进行性神经系统疾病。我们现在寻求建立在我们以前的工作，以进一步了解过氧化物酶体-ER相互作用是如何调节的，以及它们如何影响脂质代谢。我们将使用哺乳动物细胞来回答诸如ACBD 5和VAPB结合是如何实现的，在什么条件下结合被打开和关闭，以及控制这种情况如何以及何时发生的系统是什么等问题。了解这一点将使我们能够寻找策略，这将使我们能够调节这些相互作用，可能导致未来的治疗方法，以恢复细胞器的合作和脂质平衡的病理条件下，细胞器接触被破坏。这是一个非常令人兴奋的生物学领域，它不仅有望提供细胞中单个细胞器相互作用事件如何发生的基本见解，而且还将细胞器通信失败与疾病（包括与年龄相关的疾病）联系起来。

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.