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：
10116429
负责人：
fei wang
金额：
$ 34.39万
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/10116429
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.

项目摘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业程序来自二倍体祖细胞的游戏。尽管泛素/蛋白酶体系统在减数分裂中的作用具有描述得很好，自噬的潜力在减数分裂划分期间介导了不同的步骤仍然出乎意料。我的实验室最近做出了新的发现，即自噬，是通往溶酶体的保守途径退化，对于忠实的减数分裂染色体隔离和减数分裂的萌芽至关重要酵母。我们进一步确定了这种减数分裂自噬活性的主要目标-RIM4，一种减数分裂特异性的RNA 结合蛋白（RBP）适应淀粉样蛋白状态并隔离编码特定蛋白的mRNA 参与减数分裂调节，染色体分离和孢子形成（细胞因子）。重要的是，期间减数分裂和早期胚胎细胞的发育，基因表达在转录后受到主要调节使用由RBP选择性约束的母体mRNA。减数分裂蛋白的暂时翻译，哪些控制减数分裂细胞的进展，由这些RBP通过很大的未知和变化来调节机制[10]。我们的发现揭示了自噬和减数分裂翻译之间的新颖联系。在此外，我们发现自噬会降解一组与纺锤体身体相关的蛋白质（SPB，酵母中心体）结构和功能，这对于减数分裂和孢子形成至关重要。我们提出的特定蛋白质自噬降解，例如RIM4淀粉样蛋白骨料，SPC42 和Spo74，在多个减数分裂阶段有助于减数分裂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会融合以协调减数分裂和孢子形。该提案的主要目标是（1）机械剖析自噬如何调节RIM4 降解及其对RIM4 mRNA靶标的减数分裂基因表达的影响；（2）揭示减数分裂自噬在限制每个细胞的SPB数量中的作用。这种理解将揭示新的原则潜在的mRNA特异性翻译控制和减数分裂调节，如果自噬参与了人类减数分裂也为预防染色体疾病的策略提供了信息，例如特纳综合征（单色） X，频率：1/2,500名新生儿）[11]和唐氏综合症（三体疾病，频率：1/800新生儿）[12]。这项研究还将阐明治疗剂的设计，以清除缺失的淀粉样蛋白骨料与神经变性有关（例如，阿尔茨海默氏病中的淀粉样蛋白β）。这项赠款提议：（1）阐明自噬如何促进RIM4降解以调节减数分裂翻译；（2）调查自噬如何调节减数分裂过程中的酵母中心体动力学。