Exploring New Players in Proteostasis

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Maintaining protein homeostasis, also known as proteostasis, is fundamentally important for all processes in biology. It is therefore not surprising, that cells contain an entire fleet of chaperones and proteases, which are tasked to correctly fold and target nascent proteins, prevent unsolicited protein misfolding and protect proteins against irreversible aggregation. Unfortunately, however, disturbances in the activity or composition of the proteostasis network do occur, and can be devastating, particularly in their relationship to amyloid- related protein folding diseases, including Alzheimer’s and Parkinson’s disease. My lab focuses on two different mechanisms that are involved in maintaining protein homeostasis. My first major project centers on the functional activity of polyphosphate, a highly conserved polymer composed of long chains of phospho- anhydride bonded phosphates. Previous work from our lab demonstrated that polyP shares many features with protein chaperones, including its ability to prevent stress-specific protein aggregation, and to protect neuronal cells against amyloid toxicity by modulating disease-associated amyloid fibril formation. Most recently, we added a new function to polyP’s stress-protective repertoire by demonstrating that it undergoes liquid-liquid phase transitions with nucleoid-associated proteins, and in doing so, contributes to the silencing of genetic mobile elements in bacteria. We will now use a multipronged cell biological, biochemical and cryo- EM-based structural approach to i) understand the parameters that drives polyP to interact with proteins in these multiple different capacities, ii) test the exciting hypothesis, based on two recently solved cryoEM structures of patient-derived fibrils, that polyP is a physiologically relevant modulator of amyloidogenic processes, and iii) investigate polyP’s newly identified role as a critical component of bacterial heterochromatin. The second major research arm in my lab is centered on the hypothesis that histone-based epigenetic modifications constitute an important but vastly understudied mechanism that acts in regulating protein homeostasis. We posit that these modifications can affect proteostasis in the short term, long-term and potentially even trans-generationally. We will focus on the inheritable histone modification H3K4me3, whose global reduction has been shown by us and others to increase stress gene expression, improve stress resistance and protect organisms against amyloid-related toxicity. Our major goals are to explore the mechanism of how global changes in H3K4me3 levels can exert these consequential effects on proteostasis in general and amyloidogenic processes in particular. Our studies have the potential of adding entirely new layers of mechanisms to the regulation of protein homeostasis, and will aid in achieving the overarching goal of identifying the major players guarding the proteome and understanding how they work.