Chaperone Limitations in Prion Curing

Abstract

Amyloid promotes a dramatic transition in protein conformation that perpetuates, giving rise to a broad variety of distinct phenotypes, ranging from pathological disorders to dynamic heritable traits. Amyloid has long been thought to be resistant to clearance by the proteostasis network, but increasing evidence is challenging this view. For example, heat shock disassembles yeast prion amyloids, revealing in vivo solubilization of these aggregates. However, the exact proteostatic niche that promotes amyloid clearance is largely unknown. We identified several environmental stresses leading to prion curing via the same mechanism as heat shock and further showed that a shared characteristic was the activation of the transcription factor heat shock factor 1 (Hsf1). Strikingly, artificial Hsf1 activation interfered with heat shock-mediated prion curing, presumably due to overexpression of a nucleotide exchange factor Sse1. Limiting Sse1, which decelerates the Hsp70 cycle, promoted chaperone loading on prion aggregates and enabled artificial Hsf1 activation to resolve prion aggregates; in contrast, it impaired resolution of stress-induced aggregates and cell growth at elevated temperature. Thus, our study demonstrates that the proteostasis network, fine-tuned for optimal dissolution of non-amyloid aggregates, can be reconfigured for solubilization of amyloid by modulating the Hsp70 cycle.