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Regulation of Aberrant Protein Production

异常蛋白质生产的调节

基本信息

批准号：
10475220
负责人：
Andrey L Karamyshev
金额：
$ 30.6万
依托单位：
TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-16 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10475220
关键词：
Address Cells Complex Defect Detection Disease Enzymes Genetic Transcription Hormones Human Immunofluorescence Immunologic In Vitro Knowledge Lead Mammalian Cell Mass Spectrum Analysis Mediating Membrane Proteins Messenger RNA Modeling Molecular Monitor Mutation Northern Blotting Pathway interactions Peptide Signal Sequences Process Production Prolactin Proteins Quality Control Regulation Research Ribosomes Signal Recognition Particle Site Stress System Technology Testing Translational Repression Translations Ubiquitin Western Blotting crosslink design endonuclease human disease in vivo knock-down mRNA Transcript Degradation misfolded protein multicatalytic endopeptidase complex novel overexpression polypeptide polysome profiling prevent protein aggregation protein expression response secretory protein sensor transcriptome transcriptome sequencing

项目摘要

ABSTRACT Defective proteins result from mutations, mistakes of transcription, stress, and other factors. These aberrant proteins are often toxic and cause a number of human diseases. There are several quality control (QC) pathways in the cells: nonsense-mediated, no-stop, and no-go decays for defective mRNAs, and the ubiquitin/proteasome system for already synthesized misfolded proteins. Recently, we discovered a new QC pathway called Regulation of Aberrant Protein Production (RAPP). RAPP is a preemptive QC, it monitors proteins during their synthesis at the ribosome, senses defective proteins and degrades their mRNA templates. It is the first example of transferring information about aberrant proteins to mRNA degradation machinery. Normally, nascent polypeptides emerged from the ribosome exit tunnel interact with targeting or folding factors. When a mutation prevents these interactions, the Ago2 protein, a sensor in the RAPP response, detects the loss of these important interactions and triggers mRNA degradation. Surprisingly, Ago2 endonuclease activity is not required in the process. Thus, the molecular mechanism of RAPP is not well understood, very little is known about its mRNA degradation machinery and its substrates. The proposed project will fill these gaps in knowledge. Our hypothesis is that RAPP is a general protein quality control pathway that consists of three major steps: detection of an aberrant nascent chain complex, translational repression, and formation of specialized cytoplasmic foci for degradation of the aberrant mRNA. Our specific aims are designed to test this hypothesis and directed to (1) elucidate the mechanism by which protein expression is down-regulated in RAPP, and (2) determine whether RAPP is a general mechanism of protein quality control for secretory and membrane proteins in mammalian cells. The proposal involves application of comprehensive in vivo and in vitro approaches, including our unique technology, iPINCH, for identification of Proteins Interacting with Nascent Chains. Determining the scope and mechanism of RAPP will impact the field of protein quality control research by providing a better understanding of cellular defense against erroneous and potentially toxic proteins.

摘要

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

SRPassing Co-translational Targeting: The Role of the Signal Recognition Particle in Protein Targeting and mRNA Protection.

DOI：
10.3390/ijms22126284
发表时间：
2021-06-11
期刊：
International journal of molecular sciences
影响因子：
5.6
作者：
Kellogg MK;Miller SC;Tikhonova EB;Karamyshev AL
通讯作者：
Karamyshev AL

Defective Human SRP Induces Protein Quality Control and Triggers Stress Response.

缺陷人类SRP诱导蛋白质质量控制，并触发压力反应。

DOI：
10.1016/j.jmb.2022.167832
发表时间：
2022-11-30
期刊：
JOURNAL OF MOLECULAR BIOLOGY
影响因子：
5.6
作者：
Tikhonova, Elena B.;Guarnizo, Sneider Alexander Gutierrez;Kellogg, Morgana K.;Karamyshev, Alexander;Dozmorov, Igor M.;Karamysheva, Zemfira N.;Karamyshev, Andrey L.
通讯作者：
Karamyshev, Andrey L.

Aberrant protein targeting activates quality control on the ribosome.