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Discovery of Novel Mechanisms of Action of Ubiquitin-Like Proteins in Cellular Stress Pathways

泛素样蛋白在细胞应激途径中作用的新机制的发现

基本信息

批准号：
10581949
负责人：
Lilliana RADOSHEVICH
金额：
$ 24.97万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10581949
关键词：
Address Algorithms Animals Antibodies Autoimmune Diseases Autophagocytosis Biochemistry Bioinformatics C-terminal Catabolic Process Cells Cellular Stress Cellular Stress Response Cellular biology Coupled Data Set Disease Enzymes FRAP1 gene Future Genetic Glycylglycine Goals ISG15 gene Immune In Vitro Infection Knock-in Mouse Laboratories Lead Liver Lysine Malignant Neoplasms Metabolic Metabolism Methods Modification Neurodegenerative Disorders Nutrient Outer Mitochondrial Membrane Pathogenicity Pathway interactions Peptides Physiological Property Proteins Proteomics Role Site Stress Technology Testing Ubiquitin Ubiquitin Like Proteins Variant Work adduct biological adaptation to stress cellular targeting combat design endoplasmic reticulum stress gene repression in vivo interdisciplinary approach mutant novel overexpression parasitism peptidyl-Lys metalloendopeptidase protein aminoacid sequence protein complex response

项目摘要

PROJECT SUMMARY Eukaryotic cellular stress responses are highly conserved and precisely regulated. When these pathways malfunction there are often grave physiological consequences in the form of diseases such as cancer, neurodegenerative disease and autoimmune disorders. Ubiquitin-like modifications (UBLs) are rapid, reversible and can profoundly alter cell fate and function. Intriguingly, the majority of UBLs are involved in the cellular response to stress, in particular the response to infection, ER-stress and autophagy. Ubiquitin-like proteins share structural conservation with ubiquitin and also covalently modify target proteins, however UBLs have extremely divergent functions, which range from transcriptional repression to autophagy initiation. Unlike ubiquitin, the consequences of ISGylation or ATG12ylation on target protein fate and function are largely unknown. In this proposal, we aim to decode the post-translational landscape of the cell following eukaryotic stress responses using sophisticated proteomics strategies to address the fundamental question of how ISG15 and ATG12 alter the function of their covalent cellular targets. For ISG15, my laboratory’s recent work identified a novel role in the control of host metabolic processes and this proposal addresses how ISGylation of mTOR and other key upstream regulators of the catabolic process of autophagy tunes the metabolic and catabolic capacity of cells and animals. For ATG12, we have pioneered an in vivo genetic method coupled with cutting-edge proteomics to identify endogenous substrates of the autophagy-related ubiquitin-like protein ATG12 following induction of cellular stress pathways such as mitochondrial outer membrane permeabilization or endoplasmic reticulum stress.

项目总结真核细胞的应激反应是高度保守和精确调控的。当这些路径故障通常以癌症等疾病的形式出现严重的生理后果，神经退行性疾病和自身免疫性疾病。泛素样修饰(UBL)是快速、可逆的可以深刻地改变细胞的命运和功能。有趣的是，大多数UBL都与细胞对压力的反应，特别是对感染、内质网应激和自噬的反应。泛素样蛋白共有与泛素保持结构保守，还可以共价修饰靶蛋白，但UBL具有极强的不同的功能，从转录抑制到自噬启动。与泛素不同， ISG化或ATG12化对靶蛋白命运和功能的影响在很大程度上是未知的。在这建议，我们的目标是解码真核应激反应后细胞的翻译后图景使用复杂的蛋白质组学策略解决ISG15和ATG12如何改变这一根本问题它们的共价细胞靶标的功能。对于ISG15，我的实验室最近的工作确定了在控制宿主代谢过程中的一个新角色，这提案阐述了mTOR的ISG化和分解代谢过程的其他关键上游调节因子是如何自噬调节细胞和动物的新陈代谢和分解代谢能力。对于ATG12，我们开创了体内遗传方法与尖端蛋白质组学相结合的方法来识别细胞诱导后自噬相关泛素样蛋白ATG12的内源性底物应激途径，如线粒体外膜通透性或内质网应激。