Organelle proteostasis in cellular quiescence and growth

Proteostasis refers to the balance of protein synthesis, folding, and degradation. About a third of all proteins are handled by membranous organelles and the homeostasis of these proteins is referred to as organelle proteostasis. The working hypothesis of this project is that organelle integrity is essential for cell growth and quiescence. One of the key organelles involved in proteostasis is the endoplasmic reticulum (ER). The ER is responsible for protein folding and quality control, and is also involved in the degradation of misfolded proteins. When the ER is under stress, it can activate the unfolded protein response (UPR), which helps to restore proteostasis. We will investigate how ER-proteostasis is affected by the transition between growth and quiescence. Conversely, we will disrupt ER-proteostasis and determine the ability of cells to transition between growth and quiescence. Synthesis of proteins depends on uptake of amino acids and nutrients, which is mediated by transporter proteins that are found at the cell surface. Actively growing cells, need to maintain high levels of such nutrient transporters. However, it is less clear how cells downregulate these transporters when entering quiescence and whether the proteostasis of other organelles affects these transporters. Another organelle involved in proteostasis is the lysosome. The lysosome is responsible for the degradation of proteins, lipids, and other molecules. To maintain proteostasis, lysosome function, size and number must adapt to changes in cellular needs. Lysosomes are also platforms for signaling of mTORC1, a kinase complex that is a major regulator of cell growth. We will investigate the crosstalk of lysosomes and mTORC1 signaling with ER function and with nutrient uptake as cells transition between growth and quiescence. Because alterations of proteostasis are of relevance for diseases such as cancer and neurodegeneration, we believe that the insights gained from this project will be crucial for understanding the basic biology of cells and to obtain a deeper understanding of diseases mechanisms.