Protect and recycle: how cells regulate dormancy

Our research is focused on elucidating how cell growth and division are regulated in space and time, in particular by selective degradation of cellular components. Eukaryotic cells use autophagy and the ubiquitin-​proteasome system (UPS) to ensure cellular homeostasis, and recycle excess and non-essential components in response to nutrient starvation. Yet, mechanisms must exist that protect essential cellular components to resume cell growth after stress release. However, despite the fundamental relevance in health and disease, little is known how these counteracting processes are regulated and coordinated in starved and dormant cells. To address these fundamental questions, we use yeast and mammalian cells to investigate how cells protect essential cellular components such as ribosomes and key metabolic enzymes. Using yeast pyruvate kinase (PK) Cdc19 as a paradigm, we recently found that this enzyme forms reversible fibers which resemble amyloid-like structures. Amyloids were long viewed as irreversible, pathological aggregates, often associated with neurodegenerative diseases. However, recent insights challenge this view, providing evidence that reversible amyloids form upon stress conditions and fulfil crucial cellular functions. Yet, the molecular mechanisms regulating functional amyloids and the differences to their pathological counterparts remain poorly understood. We demonstrate that both yeast and human PK (PKM2) form reversible aggregates through a pH-sensitive amyloid core. Stress-induced cytosolic acidification promotes aggregate formation via protonation of specific glutamate or histidine residues within the amyloid core motif. Mutations mimicking protonation result in constitutive PK aggregation, while conversely a non-protonatable PK mutant remains soluble even during stress conditions. Physiological PK aggregation is coupled to metabolic rewiring and glycolysis arrest, and mis-regulation of this process results in severe growth defects.

 Our work thus unravels an evolutionarily conserved and potentially widespread molecular mechanism governing amyloid functionality and reversibility, triggered by a physiological pH change during stress.