Systematic analysis of post-translational regulation of autophagy protease ATG4B

自噬蛋白酶ATG4B翻译后调控的系统分析

• 批准号: BB/J015881/1
• 负责人: Robin Ketteler
• 金额: $ 32.54万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FJ015881%2F1
• 关键词: Systematic; analysis; post; translational; regulation

Autophagy can be regarded as a cellular self-cleaning process through which damaged and potentially toxic components are removed through degradation. This process is involved in the clearance of protein aggregates (as for example in neurodegenerative disorders), damaged organelles (induced by cellular stresses or extracellular toxins) or pathogens (such as bacteria or viruses). In addition, autophagy counteracts the deleterious effects associated with ageing as it helps clear the accumulation of toxic protein products and damaged material that accumulates over time. Accordingly, it is of high importance that this process is tightly controlled. Dysregulation of autophagy is commonly associated with severe diseases that can lead to cancer, Parkinson's disease or Alzheimer's disease, just to name a few. Autophagy can be induced through multiple mechanisms, including starvation, hypoxia, DNA damage or pathogen infection resulting in the formation of a double-membrane structure, the autophagosome. The autophagosome can remove defective organelles or complexes from cells and in most cases rescues the cell from potential harmful effects of the initial stressor. To understand these complex physiological conditions, it is of high importance to identify the molecular components involved and understand their interactions and regulation. The autophagy machinery has been well characterized both in human cells and in yeast. There is one main question remaining in the field: that is to characterize the molecular mechanisms by which these proteins interact. Further, there is a huge interest in drug discovery to utilize this knowledge to develop therapeutic strategies for diseases associated with autophagy. Here, we aim to identify the molecular regulation of one of the key enzymes involved in autophagy, ATG4B. In order to identify the regulation of this protein, we will make use of recent technical advances in genomics and proteomics and use a combination of high-throughput screening technologies and proteomic profiling. There will be a huge benefit in identifying specific molecular targets within the autophagy pathway as this will enable more focused drug discovery efforts. This project will shed light onto the signaling cascades that control an early step in autophagy and will provide to a general understanding of autophagy that will lead to the identification of potential novel therapeutic targets.

自噬可以被认为是细胞的自我清洁过程，通过该过程，受损的和潜在的有毒成分通过降解被去除。该过程涉及蛋白质聚集体（例如在神经退行性疾病中）、受损细胞器（由细胞应激或细胞外毒素诱导）或病原体（例如细菌或病毒）的清除。此外，自噬抵消了与衰老相关的有害影响，因为它有助于清除有毒蛋白质产物的积累和随着时间的推移而积累的受损物质。因此，严格控制该过程是非常重要的。自噬的失调通常与严重的疾病有关，这些疾病可能导致癌症，帕金森病或阿尔茨海默病，仅举几例。自噬可以通过多种机制诱导，包括饥饿、缺氧、DNA损伤或病原体感染，导致形成双膜结构，即自噬体。自噬体可以从细胞中去除有缺陷的细胞器或复合物，并且在大多数情况下可以将细胞从初始压力源的潜在有害影响中拯救出来。为了了解这些复杂的生理条件，识别所涉及的分子组分并了解它们的相互作用和调节是非常重要的。自噬机制在人类细胞和酵母中都得到了很好的表征。在该领域仍然存在一个主要问题：即表征这些蛋白质相互作用的分子机制。此外，人们对药物发现产生了巨大的兴趣，以利用这些知识来开发与自噬相关的疾病的治疗策略。在这里，我们的目标是确定参与自噬的关键酶之一ATG 4B的分子调节。为了确定这种蛋白质的调控，我们将利用基因组学和蛋白质组学的最新技术进展，并结合使用高通量筛选技术和蛋白质组学分析。在自噬途径中识别特定的分子靶点将有巨大的好处，因为这将使药物发现工作更加集中。该项目将揭示控制自噬早期步骤的信号级联，并将提供对自噬的一般理解，从而识别潜在的新型治疗靶点。

项目成果

A new age in functional genomics using CRISPR/Cas9 in arrayed library screening.

• DOI: 10.3389/fgene.2015.00300
• 发表时间: 2015
• 期刊: Frontiers in genetics
• 影响因子: 3.7
• 作者: Agrotis A;Ketteler R
• 通讯作者: Ketteler R

Corrigendum: Image-based siRNA screen to identify kinases regulating Weibel-Palade body size control using electroporation.

• DOI: 10.1038/sdata.2017.86
• 发表时间: 2017-06-27
• 期刊: Scientific data
• 影响因子: 9.8
• 作者: Ketteler R;Freeman J;Stevenson N;Ferraro F;Bata N;Cutler DF;Kriston-Vizi J
• 通讯作者: Kriston-Vizi J

Autophagy gene expression profiling identifies a defective microtubule-associated protein light chain 3A mutant in cancer.

• DOI: 10.18632/oncotarget.9754
• 发表时间: 2016-07-05
• 期刊: Oncotarget
• 作者: Costa JR;Prak K;Aldous S;Gewinner CA;Ketteler R
• 通讯作者: Ketteler R

Redundancy of human ATG4 protease isoforms in autophagy and LC3/GABARAP processing revealed in cells

细胞中揭示自噬和 LC3/GABARAP 加工中人类 ATG4 蛋白酶亚型的冗余

• DOI: 10.6084/m9.figshare.7610663
• 发表时间: 2019
• 作者: Agrotis A

Ribose 5-phosphate isomerase inhibits LC3 processing and basal autophagy.

• DOI: 10.1016/j.cellsig.2016.06.015
• 发表时间: 2016-09
• 期刊: Cellular signalling
• 影响因子: 4.8
• 作者: Heintze J;Costa JR;Weber M;Ketteler R
• 通讯作者: Ketteler R