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

了解细胞器通讯在细胞脂质代谢和发育过程调节中的分子机制

• 批准号: BB/W015420/1
• 负责人: Michael Schrader
• 金额: $ 66.12万
• 依托单位: UNIVERSITY OF EXETER
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FW015420%2F1
• 关键词: Understanding; molecular; mechanisms; organelle; communication

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.

人类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室，称为细胞器。虽然每种类型的细胞器都有自己的特定角色，但它们也构成了更广泛的网络的一部分，并且必须根据细胞的需要相互通信以协调它们的功能。依赖于这种合作的细胞的一个基本功能是脂质分子的产生和加工，以1）调节细胞能量产生; 2）分解有毒脂质以避免其积累;以及3）为细胞制造重要的构建块，例如在神经细胞中至关重要的称为缩醛磷脂的脂质。对产生和加工脂质至关重要的两种细胞器是内质网（ER）和过氧化物酶体，它们共同形成这些分子的“代谢中心”。脂质在两者之间的物理接触部位传递。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。在我们以前的工作中，我们确定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。这包括过氧化物酶体上的蛋白质ACBD 4和ACBD 5，它们都可以直接与脂质结合。他们属于一个大家族的脂质结合蛋白，这是没有得到很好的探索，但最近已被链接到人类疾病的患者在这些蛋白质的缺陷已经确定。最近，我们发现，一种特定形式的ACBD 4，称为ACBD 4. 3，被发现在另一个细胞器（细胞核），但也在过氧化物酶体，它结合ACBD 5。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，响应性地改变细胞产生的蛋白质。据我们所知，这是第一次核蛋白也存在于过氧化物酶体中，这表明这两个细胞器之间存在一种由ACBD 4.3介导的新的通信渠道。我们认为ACBD4.3在过氧化物酶体和细胞核中起着重要作用，协调细胞内的脂质代谢。特别是，ACBD4.3可以与脂质结合的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的协调方式改变其脂质加工。为了探索过氧化物酶体，ER和细胞核之间这种令人兴奋的新通讯联系的机制和功能，我们将使用哺乳动物细胞来研究1）ACBD 4和5蛋白如何一起工作以控制过氧化物酶体-ER相互作用; 2）ACDB 4蛋白在细胞核中的功能是什么; 3）ACBD 4蛋白如何影响细胞脂质代谢并协调细胞核和过氧化物酶体活性。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，以斑马鱼为模型，因为它们具有许多实验优势。总之，这一提议将为我们对细胞脂质代谢和细胞器通信网络的基本调节提供重要的新见解，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。

项目成果

Generation of Reporter Cell Lines for Endogenous Expression Analysis of Peroxisomal Proteins.

用于过氧化物酶体蛋白内源表达分析的报告细胞系的生成。

• DOI: 10.1007/978-1-0716-3048-8_18
• 发表时间: 2023
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Silva BSC

Immunolabeling for Detection of Endogenous and Overexpressed Peroxisomal Proteins in Mammalian Cells.

用于检测哺乳动物细胞中内源性和过度表达的过氧化物酶体蛋白的免疫标记。

• DOI: 10.1007/978-1-0716-3048-8_4
• 发表时间: 2023
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Schrader TA

Differential roles for ACBD4 and ACBD5 in peroxisome-ER interactions and lipid metabolism.

• DOI: 10.1016/j.jbc.2023.105013
• 发表时间: 2023-08
• 期刊: JOURNAL OF BIOLOGICAL CHEMISTRY
• 影响因子: 4.8
• 作者: Costello, Joseph L.;Koster, Janet;Silva, Beatriz S. C.;Worthy, Harley L.;Schrader, Tina A.;Hacker, Christian;Passmore, Josiah;Kuypers, Frans A.;Waterham, Hans R.;Schrader, Michael
• 通讯作者: Schrader, Michael

Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders.

双等位基因 ACBD6 变异会导致神经发育综合征，并伴有进行性和复杂的运动障碍。

• DOI: 10.1093/brain/awad380
• 发表时间: 2024
• 期刊: Brain : a journal of neurology
• 作者: Kaiyrzhanov,Rauan;Rad,Aboulfazl;Lin,Sheng-Jia;Bertoli-Avella,Aida;Kallemeijn,WouterW;Godwin,Annie;Zaki,MahaS;Huang,Kevin;Lau,Tracy;Petree,Cassidy;Efthymiou,Stephanie;Karimiani,EhsanGhayoor;Hempel,Maja;Normand,ElizabethA;Rud
• 通讯作者: Rud

The peroxisome: an update on mysteries 3.0.

• DOI: 10.1007/s00418-023-02259-5
• 发表时间: 2024-02
• 期刊: Histochemistry and cell biology
• 影响因子: 2.3