Understanding the molecular mechanisms of organelle communication in the regulation of cellular lipid metabolism and developmental processes

人类细胞必须执行许多复杂的功能才能维持生命。为了有效地管理所有这些过程，细胞被分成许多不同的隔室，称为细胞器。虽然每种类型的细胞器都有自己特定的角色，但它们也构成了一个更广泛的网络的一部分，它们必须相互通信，以根据细胞的需要协调它们的功能。依赖这种合作的细胞的一个基本功能是产生和处理脂分子，以1)调节细胞能量的产生；2)分解有毒的脂类以避免它们的积累；3)为细胞制造重要的构件，如在神经细胞中至关重要的称为血浆原的脂类。产生和处理脂类的两个重要细胞器是内质网(ER)和过氧化物体，它们共同形成这些分子的“代谢中枢”。在身体接触的地方，脂质在两者之间传递。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。在我们之前的工作中，我们确定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。这包括过氧化体上的ACBD4和ACBD5蛋白，这两种蛋白都可以直接与脂质结合。它们属于一个大的脂结合蛋白家族，目前还没有得到很好的研究，但最近随着这些蛋白缺陷的患者被发现与人类疾病有关。最近，我们发现ACBD4的一种特殊形式ACBD4，称为ACBD4.3，在另一个细胞器(核)中被发现，但也在它与ACBD5结合的过氧化体中被发现。细胞核是细胞功能的主要调节器，它根据细胞的需要和环境，相应地改变细胞产生的蛋白质。据我们所知，这是第一次在过氧化物体中也存在核蛋白，这表明在这两个细胞器之间存在一种由ACBD4.3介导的新的通讯渠道。我们认为，ACBD4.3在过氧化体和细胞核中都扮演着重要的角色，协调细胞内的脂肪代谢。特别是，ACBD4.3可以与脂类结合的事实增加了一种有趣的可能性，即它可能能够将关于细胞当前脂质含量的信息传递到多个细胞器，确保细胞根据细胞的需要以适当的、协调的方式改变其脂质处理。为了探索这种令人兴奋的新的在过氧体、内质网和细胞核之间的通信链接的机制和功能，我们将使用哺乳动物细胞来研究1)ACBD4和5种蛋白质如何共同作用来控制过氧体-内质网的相互作用；2)ACDB4蛋白在细胞核中的功能是什么；3)ACBD4蛋白如何影响细胞的脂代谢，协调核和过氧化体的活动。一旦我们在细胞水平上了解了这一点，我们就想利用斑马鱼的许多实验优势，研究这种交流和调节对整个生命系统的发育和新陈代谢的影响。综上所述，这一提议将使我们对细胞脂代谢和细胞器通信网络的基本调控有重要的新见解，最终可能揭示治疗这些过程失调的年龄相关疾病的新策略。

A human cell has to carry out many complex functions to support life. To manage all these processes efficiently, cells are divided into numerous distinct compartments, known as organelles. While each type of organelle has its own specific roles, they also form part of a wider network and must communicate with each other to coordinate their functions depending on the needs of the cell. One essential function of the cell that relies on this cooperation is the production and processing of lipid molecules to 1) regulate cellular energy production; 2) break down toxic lipids to avoid their accumulation; and 3) make important building blocks for the cell, such as lipids called plasmalogens that are critically important in nerve cells.Two organelles that are vital to produce and process lipids are the endoplasmic reticulum (ER) and the peroxisome, which together form a 'metabolic hub' for these molecules. Lipids are passed between the two at sites of physical contact. 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. In our previous work, we identified the protein components that mediate the peroxisome-ER interaction in human cells. This includes the proteins ACBD4 and ACBD5 at peroxisomes, which can both bind to lipids directly. They belong to a large family of lipid binding proteins, which are not well explored, but have recently been linked to human disease as patients with defects in these proteins have been identified.Recently, we discovered that one specific form of ACBD4, called ACBD4.3, is found in another organelle (the nucleus), but also at peroxisomes where it binds to ACBD5. The nucleus is a master regulator of cell function by responsively changing which proteins the cell produces, depending on its needs and environment. This, to our knowledge, is the first time a nuclear protein is also present at peroxisomes, indicating that there is a novel channel of communication between these two organelles that is mediated by ACBD4.3. We propose that ACBD4.3 plays important roles at both peroxisomes and the nucleus, to orchestrate cell-wide lipid metabolism. In particular, the fact that ACBD4.3 can bind to lipids raises the intriguing possibility that it may be able to relay information about the current lipid content of the cell to multiple organelles, ensuring the cell alters its lipid processing in an appropriate, coordinated fashion depending on the needs of the cell.To explore the mechanism and function of this exciting new communication link between peroxisomes, the ER and the nucleus, we will use mammalian cells to investigate 1) how ACBD4 and 5 proteins work together to control the peroxisome-ER interaction; 2) what the function of ACDB4 proteins in the nucleus is, and 3) how ACBD4 proteins impact on cellular lipid metabolism and coordinate nuclear and peroxisomal activities. Once we understand this on a cellular level, we then want to 4) investigate the consequences of this communication and regulation on the development and metabolism of a whole living system, using zebrafish as a model due to their many experimental advantages. Together, this proposal will give us crucial new insights into the fundamental regulation of cellular lipid metabolism and organelle communication networks, which could ultimately reveal new strategies to treat age-related disorders where these processes are dysregulated.