Reversible amyloids of pyruvate kinase couple cell metabolism and stress granule disassembly

Cereghetti et al. report that the glycolytic metabolite fructose-1,6-bisphosphate initiates the disassembly of amyloids formed by the yeast pyruvate kinase Cdc19 to resume ATP production during stress recovery. Cells respond to stress by blocking translation, rewiring metabolism and forming transient messenger ribonucleoprotein assemblies called stress granules (SGs). After stress release, re-establishing homeostasis and disassembling SGs requires ATP-consuming processes. However, the molecular mechanisms whereby cells restore ATP production and disassemble SGs after stress remain poorly understood. Here we show that upon stress, the ATP-producing enzyme Cdc19 forms inactive amyloids, and that their rapid re-solubilization is essential to restore ATP production and disassemble SGs in glucose-containing media. Cdc19 re-solubilization is initiated by the glycolytic metabolite fructose-1,6-bisphosphate, which directly binds Cdc19 amyloids, allowing Hsp104 and Ssa2 chaperone recruitment and aggregate re-solubilization. Fructose-1,6-bisphosphate then promotes Cdc19 tetramerization, which boosts its activity to further enhance ATP production and SG disassembly. Together, these results describe a molecular mechanism that is critical for stress recovery and directly couples cellular metabolism with SG dynamics via the regulation of reversible Cdc19 amyloids.

Automated summary

The glycolytic metabolite fructose-1,6-bisphosphate is able to initiate the disassembly of inactive amyloids formed by Cdc19 during stress, leading to the restoration of ATP production and disassembly of stress granules (SGs) in yeast cells. This mechanism directly links cellular metabolism with SG dynamics, and plays a critical role in stress recovery by promoting Cdc19 re-solubilization and enhancing ATP production.