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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：
10797369
负责人：
Lilliana RADOSHEVICH
金额：
$ 10.59万
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/10797369
关键词：
Address Algorithms Animals Antibodies Autoimmune Diseases Autophagocytosis Biochemistry Bioinformatics C-terminal Catabolic Process Cell Membrane Permeability Cells Cellular Stress Cellular biology Coupled Data Set Disease Enzymes FRAP1 gene Future Genetic Glycylglycine Goals ISG15 gene Immune In Vitro Infection Knock-in Mouse Laboratories 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 programs 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.

项目摘要真核细胞应激反应是高度保守和精确调控的。当这些途径功能障碍通常会导致严重的生理后果，例如癌症，神经变性疾病和自身免疫性疾病。泛素样修饰（UBLs）是快速、可逆的，并能深刻地改变细胞的命运和功能。有趣的是，大多数UBL参与细胞内的对应激的反应，特别是对感染、ER应激和自噬的反应。类泛素蛋白泛素结构保守性以及共价修饰的靶蛋白，然而UBL具有极其不同的功能，其范围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。在这我们的目标是解码真核生物应激反应后细胞的翻译后景观使用复杂的蛋白质组学策略来解决ISG15和ATG12如何改变的基本问题，它们的共价靶细胞的功能。对于ISG15，我的实验室最近的工作确定了它在控制宿主代谢过程中的新作用，该提案解决了mTOR和其他关键上游调节因子的ISGylation如何分解代谢过程，自噬调节细胞和动物的代谢和分解代谢能力。对于ATG12，我们开创了一种结合尖端蛋白质组学的体内遗传方法，自噬相关的泛素样蛋白ATG 12的内源性底物诱导细胞凋亡后，应激途径如线粒体外膜透化或内质网应激。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Host factor Rab11a is critical for efficient assembly of influenza A virus genomic segments.

DOI：
10.1371/journal.ppat.1009517
发表时间：
2021-05
期刊：
PLoS pathogens
影响因子：
6.7
作者：
Han J;Ganti K;Sali VK;Twigg C;Zhang Y;Manivasagam S;Liang CY;Vogel OA;Huang I;Emmanuel SN;Plung J;Radoshevich L;Perez JT;Lowen AC;Manicassamy B
通讯作者：
Manicassamy B

Ring finger protein 213 assembles into a sensor for ISGylated proteins with antimicrobial activity.

DOI：
10.1038/s41467-021-26061-w
发表时间：
2021-10-01
期刊：
Nature communications
影响因子：
16.6
作者：
Thery F;Martina L;Asselman C;Zhang Y;Vessely M;Repo H;Sedeyn K;Moschonas GD;Bredow C;Teo QW;Zhang J;Leandro K;Eggermont D;De Sutter D;Boucher K;Hochepied T;Festjens N;Callewaert N;Saelens X;Dermaut B;Knobeloch KP;Beling A;Sanyal S;Radoshevich L;Eyckerman S;Impens F
通讯作者：
Impens F

Identification of the MuRF1 Skeletal Muscle Ubiquitylome Through Quantitative Proteomics.

DOI：
10.1093/function/zqab029
发表时间：
2021
期刊：
Function (Oxford, England)
影响因子：
0
作者：
Baehr LM;Hughes DC;Lynch SA;Van Haver D;Maia TM;Marshall AG;Radoshevich L;Impens F;Waddell DS;Bodine SC
通讯作者：
Bodine SC

Contrasting roles of MERS-CoV and SARS-CoV-2 internal proteins in pathogenesis in mice.

DOI：
10.1128/mbio.02476-23
发表时间：
2023-12-19
期刊：
mBio
影响因子：
6.4
作者：
通讯作者：

Listeriolysin S: A bacteriocin from Listeria monocytogenes that induces membrane permeabilization in a contact-dependent manner.

DOI：
10.1073/pnas.2108155118
发表时间：
2021-10-05
期刊：
Proceedings of the National Academy of Sciences of the United States of America
影响因子：
11.1
作者：
Meza-Torres J;Lelek M;Quereda JJ;Sachse M;Manina G;Ershov D;Tinevez JY;Radoshevich L;Maudet C;Chaze T;Giai Gianetto Q;Matondo M;Lecuit M;Martin-Verstraete I;Zimmer C;Bierne H;Dussurget O;Cossart P;Pizarro-Cerdá J
通讯作者：
Pizarro-Cerdá J