Mechanistic dissection of a novel meiotic exit regulation by autophagy

自噬新型减数分裂退出调节的机制剖析

基本信息

批准号：
10357891
负责人：
fei wang
金额：
$ 34.44万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
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：
2020-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10357891
关键词：
Acute Address Aging Alzheimer&apos s Disease Amyloid Amyloid beta-Protein Autophagocytosis Basic Science Binding Biochemical Biochemistry Biological Models Cell Death Cell division Cells Centrosome Chromosome Segregation Congenital chromosomal disease Coupled Cyclins Cytokinesis Defect Development Diploidy Disease Dissection Down Syndrome Event Feedback Frequencies Gametogenesis Gene Expression Gene Targeting Genes Genetic Genetic Transcription Germ Cells Goals Grant Haploidy Human Laboratories Lead Life Light Link Mass Spectrum Analysis Maternal Messenger RNA Mediating Meiosis Membrane Membrane Proteins Messenger RNA Molecular Mutagenesis Nerve Degeneration Neurons Newborn Infant Pathway interactions Personal Communication Phenotype Phosphorylation Phosphotransferases Play Prevention strategy Process Production Proteins Proteolysis RNA Binding RNA-Binding Proteins Regulation Reporting Repression Role SNAP receptor Saccharomyces cerevisiae Saccharomycetales Science Set protein Sexual Reproduction Sister Chromatid Structure Surface System Therapeutic Translations Turner&apos s Syndrome Ubiquitin Universities Work Yeasts cellular imaging design girls imaging approach improved inhibition of autophagy membrane biogenesis multicatalytic endopeptidase complex mutant novel nuclear division premature prevent programs ribosome profiling segregation spindle pole body stem cells

项目摘要

PROJECT SUMMARY Targeted proteolysis is essential for regulating meiosis, the specialized program that produces haploid gametes from diploid progenitor cells. Although the role of the ubiquitin/proteasome system in meiosis has been well-described, the potential of autophagy to mediate distinct steps during the meiotic divisions remains unexplored. My laboratory recently made the novel discovery that autophagy, a conserved pathway to lysosomal degradation, is essential for faithful meiotic chromosome segregation and meiosis completion in budding yeast. We further identified a major target of this meiotic autophagy activity — Rim4, a meiosis-specific RNA binding protein (RBP) that adapts an amyloid-like state and sequesters mRNAs encoding specific proteins involved in meiotic regulation, chromosome segregation and sporulation (cytokinesis). Importantly, during meiotic and early embryotic cell development, gene expression is primarily regulated post-transcriptionally using maternal mRNAs that are selectively bound by RBPs. The temporal translation of meiotic proteins, which control meiotic cell progression, is regulated by these RBPs through largely unknown and varied mechanisms [10]. Our finding reveals a novel link between autophagy and meiotic translation. In addition, we discovered that autophagy degrades a set of proteins that are associated with spindle pole body (SPB, the yeast centrosome) structure and function, which is essential for both meiosis and sporulation. We propose that autophagic degradation of specific proteins, e.g. Rim4 amyloid-like aggregates, Spc42 and Spo74, at multiple meiotic stages contributes to meiosis-programed translational control and meiosis-coupled SPB dynamics. These novel roles of selective autophagy converge to coordinate meiosis and sporulation. The major goals of this proposal are (1) to mechanistically dissect how autophagy regulates Rim4 degradation and what effects this has on meiotic gene expression of Rim4 mRNA targets; and (2) to reveal the role of meiotic autophagy in restraining the number of SPB per cell. Such understanding will reveal new principles underlying mRNA-specific translational control and meiotic regulation and, if autophagy is involved in human meiosis as well, inform strategies for prevention of chromosomal disorders, e.g. Turner syndrome (monosomy X, frequency: 1/2,500 newborn girls) [11] and Down syndrome (trisomy 21, frequency: 1/800 newborns) [12]. This study will also shed light on the design of therapeutics to clear deleterious amyloid-like aggregates associated with neurodegeneration (e.g. amyloid beta in Alzheimer’s disease). This grant proposes to: (1) Elucidate how autophagy promotes Rim4 degradation to regulate meiotic translation; and (2) Investigate how autophagy regulates yeast centrosome dynamics during meiosis.

项目概要靶向蛋白水解对于调节减数分裂至关重要，减数分裂是产生单倍体的专门程序尽管泛素/蛋白酶体系统在减数分裂中的作用已经从二倍体祖细胞中产生。已被充分描述，自噬在减数分裂过程中介导不同步骤的潜力仍未被探索。我的实验室最近有了一个新发现，即自噬是溶酶体的保守途径降解，对于出芽时忠实的减数分裂染色体分离和减数分裂完成至关重要我们进一步确定了这种减数分裂自噬活性的主要靶标——Rim4，一种减数分裂特异性 RNA。结合蛋白 (RBP)，适应淀粉样蛋白样状态并隔离编码特定蛋白的 mRNA 重要的是，参与减数分裂调节、染色体分离和孢子形成（细胞分裂）。减数分裂和早期胚胎细胞发育中，基因表达主要受转录后调节使用被 RBP 选择性结合的母体 mRNA 减数分裂蛋白的时间翻译，控制减数分裂细胞进展的 RBP 通过很大程度上未知和多样的方式进行调节机制[10]。我们的发现揭示了自噬和减数分裂翻译之间的新联系。此外，我们发现自噬会降解一组与纺锤体极体相关的蛋白质（SPB，酵母中心体）的结构和功能，对于减数分裂和孢子形成至关重要。提出特定蛋白质的自噬降解，例如 Rim4 淀粉样蛋白样聚集体、Spc42 和 Spo74，在多个减数分裂阶段有助于减数分裂程序化的翻译控制和减数分裂耦合的 SPB 动力学。选择性自噬的这些新作用集中在协调减数分裂上。和孢子形成。该提案的主要目标是（1）机械地剖析自噬如何调节 Rim4 降解及其对 Rim4 mRNA 靶标减数分裂基因表达的影响；以及 (2) 揭示减数分裂自噬在抑制每个细胞 SPB 数量方面的作用将揭示新原理。潜在的 mRNA 特异性翻译控制和减数分裂调节，如果自噬参与人类减数分裂也为预防染色体疾病（例如特纳综合征）提供了信息。 X，频率：1/2,500 新生儿女孩）[11] 和唐氏综合症（21 三体，频率：1/800 新生儿）[12]。这项研究还将揭示清除有害的淀粉样蛋白样聚集物的治疗方法的设计与神经退行性疾病相关（例如阿尔茨海默氏病中的β淀粉样蛋白）。这项资助旨在：(1) 阐明自噬如何促进 Rim4 降解以调节减数分裂翻译；以及 (2) 研究自噬如何在减数分裂过程中调节酵母中心体动力学。