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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.

项目总结