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

• 批准号: 10569656
• 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
• 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/10569656
• 关键词: Acute; Address; Aging; Alzheimer' 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; Genes; Genetic; Germ Cells; Goals; Grant; Haploidy; Human; Laboratories; Life; 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; Protein Dephosphorylation; 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; Translational Repression; Translations; Turner' s Syndrome; Ubiquitin; Universities; Work; Yeasts; cellular imaging; design; girls; imaging approach; improved; inhibition of autophagy; membrane biogenesis; monomer; multicatalytic endopeptidase complex; mutant; novel; nuclear division; posttranscriptional; premature; prevent; programs; restraint; ribosome profiling; segregation; spindle pole body; stem cells

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 有针对性的蛋白质水解对于调节减数分裂是必不可少的，减数分裂是产生单倍体的专门程序 来自二倍体祖细胞的配子。虽然泛素/蛋白酶体系统在减数分裂中的作用已经被证实， 已经被很好地描述，自噬的潜力，介导不同的步骤，在减数分裂 仍然未被探索。 我的实验室最近有了新的发现，自噬，一种保守的途径， 降解，是必需的忠实减数分裂染色体分离和减数分裂完成的芽 酵母我们进一步确定了减数分裂自噬活性的主要靶点-Rim 4，一种减数分裂特异性RNA， 一种适应淀粉样状态并隔离编码特定蛋白质的mRNA的结合蛋白（RBP 参与减数分裂调节、染色体分离和孢子形成（胞质分裂）。重要的是，在 在减数分裂和早期胚胎细胞发育中，基因表达主要在转录后调节 使用被RBP选择性结合的母体mRNA。减数分裂蛋白质的时间翻译， 控制减数分裂细胞进程，是由这些RBP通过很大程度上未知和不同的调节 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。在 此外，我们发现自噬降解了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，这对于减数分裂和孢子形成都是必不可少的。我们 提出特异性蛋白质的自噬降解，例如Rim 4淀粉样聚集体、Spc 42 和Spo74，在多个减数分裂阶段有助于减数分裂程序的翻译控制， 减数分裂耦合SPB动力学。这些选择性自噬的新作用汇聚到协调减数分裂 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Rim 4 降解和这对Rim 4 mRNA靶点的减数分裂基因表达的影响;以及（2）揭示Rim 4 mRNA靶点的降解， 减数分裂自噬在抑制每个细胞SPB数量中的作用。这样的理解将揭示新的原理 潜在的mRNA特异性翻译控制和减数分裂调控，如果自噬参与人类 减数分裂，以及为预防染色体疾病，如特纳综合征（单体性 X，频率：12，500新生儿女孩）[11]和唐氏综合征（21三体，频率：1/800新生儿）[12]。 这项研究也将阐明治疗设计，以清除有害的淀粉样蛋白聚集体 与神经变性相关（例如阿尔茨海默病中的β淀粉样蛋白）。该补助金旨在：（1） 阐明自噬如何促进Rim 4降解以调节减数分裂翻译;和（2）研究 自噬如何调节减数分裂期间的酵母中心体动力学。