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

人体细胞必须执行许多复杂的功能来维持生命。为了有效地管理所有这些过程，细胞被分成许多不同的隔间，称为细胞器。虽然每种类型的细胞器都有自己的特定作用，但它们也构成了更广泛网络的一部分，并且必须根据细胞的需要相互沟通以协调它们的功能。细胞依赖于这种合作的一个基本功能是脂质分子的产生和加工，以调节细胞能量的产生；2)分解有毒脂质，避免其积聚；3)制造细胞的重要组成部分，比如在神经细胞中至关重要的脂质磷脂原。内质网（ER）和过氧化物酶体是产生和处理脂质至关重要的两个细胞器，它们共同构成了这些分子的“代谢中心”。脂质在两者物理接触处传递。由于过氧化物酶体异常或内质网和过氧化物酶体不能共同产生所需的脂质而导致这些过程中的缺陷，导致发育和神经缺陷的严重疾病。在我们之前的工作中，我们鉴定了在人类细胞中介导过氧化物酶体-内质网相互作用的蛋白质成分。这包括过氧化物酶体上的ACBD4和ACBD5蛋白，它们都可以直接与脂质结合。它们属于一个脂质结合蛋白大家族，尚未得到很好的探索，但最近已被发现与人类疾病有关，因为这些蛋白有缺陷的患者已被确定。最近，我们发现ACBD4的一种特殊形式，称为ACBD4.3，存在于另一个细胞器（细胞核）中，但也存在于与ACBD5结合的过氧化物酶体中。细胞核是细胞功能的主要调节器，根据细胞的需要和环境，通过响应性地改变细胞产生的蛋白质。据我们所知，这是核蛋白首次出现在过氧化物酶体中，表明这两个细胞器之间存在一种由ACBD4.3介导的新型通信通道。我们提出ACBD4.3在过氧化物酶体和细胞核中发挥重要作用，以协调细胞范围内的脂质代谢。特别是，ACBD4.3可以与脂质结合，这一事实提出了一种有趣的可能性，即它可能能够将有关细胞当前脂质含量的信息传递给多个细胞器，确保细胞根据细胞的需要以适当、协调的方式改变其脂质加工。为了探索这种令人兴奋的过氧化物酶体、内质网和细胞核之间的新通讯联系的机制和功能，我们将利用哺乳动物细胞来研究：1)ACBD4和5蛋白如何协同作用来控制过氧化物酶体-内质网相互作用；2) ACDB4蛋白在细胞核中的功能是什么，3)ACBD4蛋白如何影响细胞脂质代谢，协调细胞核和过氧化物酶体的活性。一旦我们在细胞水平上理解了这一点，我们就想研究这种交流和调节对整个生命系统的发育和代谢的影响，因为斑马鱼有许多实验优势，所以我们以斑马鱼为模型。总之，这一建议将使我们对细胞脂质代谢和细胞器通信网络的基本调节有重要的新见解，这可能最终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.