Targeting autophagic degradation techniques and potential applications in plant science
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摘要:
靶向降解技术是一类利用真核细胞内天然存在的降解机制对胞内有害物质进行特异降解、以维持和改善细胞稳态的重要技术。该技术主要通过泛素−蛋白酶体系统 (Ubiquitin-proteasome system，UPS) 和自噬−溶酶体途径 (Autophagy-lysosome pathway)，特异性清除细胞内错误折叠或聚集的蛋白质、大分子复合物、受损或老化的细胞器及一些非蛋白类物质。其中基于细胞自噬的靶向降解技术具有专一性强、底物种类广泛等诸多特征，使其成为一备受期待的技术，有望应用于神经退行性疾病、代谢性疾病等多种疾病的治疗。目前这一技术的应用潜能还远未被完全开发，特别是在植物研究领域。本综述首先详细介绍了各类基于自噬−溶酶体途径的靶向降解技术的作用机制、特点以及优势；并且结合华南农业大学李发强教授课题组的研究工作，着重介绍了设计和改造植物选择性自噬衔接蛋白方面的研究和设想，以期达到将对植物生长发育不利的因子经由细胞自噬转运并区室化隔离于液泡的目的，进而开发能够抵御病毒侵染或抵抗有害物质的农作物新品种；最后展望了靶向自噬的降解技术在植物科学研究和农业生产中的潜在应用前景和所面临的挑战。
Abstract:Targeted degradation techniques use the naturally existing degradation mechanism(s) in eukaryotic cells to specifically degrade harmful substances to maintain and improve cellular homeostasis. The techniques specifically remove misfolded or aggregated proteins, macromolecular complexes, damaged or aged organelles, and some non-protein substances via the ubiquitin-proteasome system (UPS) and the autophagy-lysosome pathway. Among these techniques, the targeting autophagic degradation techniques have many characteristics such as high target selectivity and wide substrate scope, making them promising techniques for the treatment of neurodegenerative diseases, metabolic diseases, and other diseases. At present, the application potential of these techniques is far from being fully developed, especially in the field of plant science. This review details the mechanisms, characteristics, and advantages of targeted degradation techniques based on the autophagy-lysosomal pathway. Moreover, combined with the recent research work of Professor Li Faqiang group in South China Agricultural University, this review focuses on the research of designing and modifying the autophagy adaptors to transport those factors unfavorable to plant growth and development via selective autophagy to the vacuole for compartmentation, so as to develop new crop varieties that can resist viral infection or toxic abiotic components. This review ends with a discussion of the potential applications and challenges of targeted autophagic degradation techniques in plant science and agricultural production.
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Keywords:
- Targeting degradation technique /
- Autophagy /
- Selective autophagy /
- Autophagy adaptor /
- Vacuole
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图 1 基于泛素−蛋白酶体系统和自噬−溶酶体/液泡途径的靶向降解技术
依赖于泛素−蛋白酶体系统的蛋白水解靶向嵌合体 (PROTAC) 技术可以通过蛋白酶体降解细胞内的目标蛋白；利用自噬−溶酶体/液泡降解途径的新技术有可能降解胞内蛋白、蛋白聚集体、受损或老化的细胞器、病毒等物质，包括基于巨自噬和基于分子伴侣介导的自噬(CMA) 的靶向降解技术
Figure 1. Targeted degradation techniques based on the ubiquitin-proteasome system and the autophagy-lysosome/vacuole pathway
The proteolysis-targeting chimera (PROTAC) degrades the target proteins via the ubiquitin-proteasome system. Novel techniques based on the autophagy-lysosome/vacuole pathway are anticipated to be applied to remove the target or aggregated proteins, damaged or aged organelles, and viruses, etc. The macroautophagy-based degraders and the chaperone-mediated autophagy (CMA)-based degraders are two of the examples
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图 2 基于自噬−溶酶体/液泡途径的靶向降解策略示意图
A：基于CMA的降解剂(CMA-based degrader)包括3个功能域——1个细胞膜穿透序列 (TAT)、1个靶向底物的特异配体以及1个CMA靶向模块(CTM)；利用TAT进入细胞后，降解剂可以结合底物并诱导伴侣介导的自噬进行特异性降解。B：自噬体绑定化合物ATTECs与LC3/ATG8和靶标底物(mHTT或脂滴) 相互作用，将底物连接到自噬体，以进行随后的自噬降解。C：AUTAC通过靶向底物的特异配体与底物(目标蛋白或线粒体)结合，并利用模仿鸟嘌呤衍生物的降解标签触发靶标底物的K63多泛素化 (Ub)，靶标底物随后被自噬受体SQSTM1/p62识别，招募到选择性自噬途径进行降解。D：AUTOTAC分子与靶标底物和p62衔接蛋白相互作用，进而将靶标底物通过自噬途径转运到溶酶体中进行降解。E：基于ATG8互作基序(AIM)的降解剂可以通过与靶标底物和ATG8相互作用，将底物连接到自噬体再进入液泡降解
Figure 2. Schematic diagram for the targeted degradation technique based on the autophagy-lysosome/vacuole pathway
A: The tripartite CMA-based degrader contains the cell membrane-penetrating sequence (TAT) followed by a target protein binding domain (PBD) and tandem repeats of the CMA-targeting motif (CTM); Aided by the TAT, these chimeric proteins enter the cell and bind to the target protein, resulting in specific degradation via CMA. B: The autophagosome-tethering compound (ATTEC) that interacts with both the LC3/ATG8 and the target substrates (mHTT or lipid droplets) targets the latter for autophagic clearance. C: The autophagy-targeting chimera (AUTAC) consists of a specific binder of an intracellular substrate (target protein or mitochondria) and a degradation tag (guanine derivatives) to induce K63-linked ubiquitination of the substrate; The target substrate later is recognized by the autophagy receptor SQSTM1/p62, resulting in autophagic degradation. D: The AUTOphagy-TArgeting Chimera (AUTOTAC) interacting with both the target substrate and the autophagy receptor p62, targets the cargo to lysosomes for degradation. E: The AIM (ATG8-interacting motif)-based degrader interacts with both the target substrate and the ATG8, enclosing the substrate into the autophagosome and later to the vacuole for degradation
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