Generation of heritable protein aggregates

The goal of this project is to understand how heritable protein aggregates form in a eukaryotic cell. Heritable aggregated protein assemblies in yeast and other fungi, known as fungal prions, provide a new mechanism for the inheritance and memory, as they control heritable traits that are not directly encoded in DNA sequence but are passed between generations in the form of rearranged proteins. This project will investigate how heritable aggregates are initially generated from a non-aggregated protein. Understanding the formation of heritable aggregates is important for linking environmental and physiological processes, such as cell stress, to heritable properties of cells and organisms. This may also help improve industrial applications, such as production of alcohol and biofuels by yeast. Research project will be integrated with course development, teaching and mentoring, thus contributing to education of diverse workforce in the areas of genetics, biochemistry and biotechnology. It will provide additional support for research infrastructure by strengthening interdisciplinary interactions. The unifying hypothesis tested in this project is that the ability to form a heritable aggregate in vivo is modulated by complex interactions between aggregation-prone proteins, cellular factors and environment, and is under the evolutionary pressure that is minimizing uncontrolled aggregation. This hypothesis will be tested in proposed experiments. Pathways linking environmental stress to heritable protein aggregation will be uncovered. Mechanisms underlining the abilities of some protein aggregates to promote aggregation of other proteins will be studied. Divergence of protein aggregation capabilities in evolution will be addressed. Relationships between reversible protein condensates, formed by liquid-liquid phase separation, and irreversible protein aggregates will be deciphered. Emergence of molecular features that make protein aggregates heritable will be investigated. Interactions of newly generated aggregates with stress-induced protein folding helpers, termed chaperones, will be explored. The project will employ a combination of genetic, cytological, biochemical and biophysical techniques. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.