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.
A major goal of science is to understand mechanisms of basic cell development and differentiation processes in order to use such information to design strategies to prevent disease and improve the quality of human life. This application aims to address the question of how autophagy, a key cellular degradation system, degrades an amyloid-like protein to enable meiotic cell progression. This basic research aims to provide a rationale for developing new strategies to remove or prevent deleterious amyloid-like aggregation that is ubiquitously observed in aging neurons and to prevent chromosomal disorders such as Down syndrome.
