BacNLR - Functional diversity of NLRs in multicellular bacteria

BacNLR - 多细胞细菌中 NLR 的功能多样性

• 批准号: EP/Z000092/1
• 负责人: Susan Schlimpert
• 金额: $ 221.63万
• 依托单位: John Innes Centre
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FZ000092%2F1
• 关键词: BacNLR; Functional; diversity; NLRs; multicellular

BacNLR is an ambitious high-risk/high-gain program to reveal the functional diversity of nucleotide-binding oligomerisation domain like receptors (NLRs) in multicellular bacteria that goes beyond their well-established role in eukaryotic immunity. NLRs are found in all domains of life, yet little is known about their role in bacteria because their existence has only recently been fully recognised.Unlike most bacteria, species of antibiotic-producing multicellular Streptomyces encode multiple NLRs with distinct signalling domains, suggesting that these proteins have diverse functions. We found that in Streptomyces several NLR-like proteins are linked to antibiotic production, development or share homology to eukaryotic NLRs shown to induce programmed cell death. We thereforehypothesise that NLR-signalling plays a crucial and so far unexplored role in several important cellular processes, including antibiotic production, immunity and multicellular behaviour.To reveal these novel cellular roles, I developed a method to synthetically activate NLR signalling in Streptomyces, overcoming the need to identify a specific stimulus for NLR activation. This breakthrough enables us now to study the impact of NLRs on regulating antibiotic production and to discover new and possibly unexpected cellular roles. In BacNLR, we will use bioinformatics to identify the full spectrum of NLR diversity in bacteria; determine the diverse functions of NLRs in multicellular Streptomyces and define the molecular mechanisms that underpin these functions.BacNLR will not only uncover new roles of NLR signalling but also reveal undamental new principles in the regulation of antibiotic production, providing an innovative strategy to combat the rise in drug-resistant pathogens. The gained knowledge will expand our current models about the evolution, and functional diversity of NLRs across all kingdoms and serve as a framework for engineeringNLR signalling pathways in bacteria.

BacNLR是一个雄心勃勃的高风险/高收益计划，旨在揭示多细胞细菌中核苷酸结合的寡聚化结构域样受体(NLR)的功能多样性，超出它们在真核免疫中的既定作用。NLR存在于生命的各个领域，但人们对它们在细菌中的作用知之甚少，因为它们的存在直到最近才被完全认识。与大多数细菌不同，产生抗生素的多细胞链霉菌编码多个具有不同信号域的NLR，这表明这些蛋白质具有不同的功能。我们发现，在链霉菌中，几个NLR样蛋白与抗生素的生产、发育有关，或与真核细胞的NLRs具有同源性，可诱导细胞程序性死亡。因此，我们假设NLR信号在几个重要的细胞过程中发挥着关键的作用，包括抗生素的产生、免疫和多细胞行为。为了揭示这些新的细胞角色，我开发了一种在链霉菌中合成激活NLR信号的方法，克服了识别NLR激活的特定刺激的需要。这一突破使我们现在能够研究NLRs对调节抗生素生产的影响，并发现新的和可能意想不到的细胞角色。在BacNLR中，我们将使用生物信息学来识别细菌中NLR多样性的全谱；确定NLR在多细胞链霉菌中的不同功能，并定义这些功能的分子机制。BacNLR不仅将发现NLR信号的新角色，还将揭示调控抗生素生产的基本新原理，为对抗耐药病原体的上升提供一种创新策略。所获得的知识将扩展我们目前关于NLR在所有王国的进化和功能多样性的模型，并作为在细菌中设计NLR信号通路的框架。