The Role of Heat Shock Proteins in Amyloid Body Reversal.

The ability of cells to adapt to a wide variety of stress conditions plays a critical role in various physiological and pathological settings, including development, cancer and neurological disorders. We recently reported the surprising discovery of stress-induced low complexity noncoding RNA derived from stimuli-specific loci of the ribosomal intergenic spacer (rIGSRNA); an enigmatic region of the human genome historically dismissed as "junk" DNA. We showed that low complexity rIGSRNA activate a physiological amyloidogenic program that converts the nucleolus into Amyloid Bodies: a molecular prison of immobilized proteins in an amyloid-like state. This conserved post-translational regulatory pathway enables cells to rapidly and reversibly store an array of endogenous proteins in Amyloid-bodies and enter quiescence in response to severe environmental insults. While many membrane-less compartments have been described as liquid-like (e.g., stress granules, P-bodies, germ cell granules), our discovery of Amyloid-bodies provided evidence of an amyloidogenic process that can physiologically transition biological matter to a solid-like state. The ability of mammalian cells to efficiently dissemble Amyloid-bodies raises a fundamental question: Are mammalian cell disaggregases involved in Amyloid-body disassembly? Here, we show that Amyloid-bodies undergo a multi-step process solid-to-liquid-phase transition to release sequestered proteins and restore nucleolar functions. An RNAi screened identified key heat shock proteins (hsps) that remodel Amyloid-bodies back to the liquid nucleoli on stress termination. The composition of mammalian disaggregases differs considerably from non-metazoans and those involved in disassembly of pathological amyloids in vitro. Activation of mammalian disaggregases and Amyloid-body disassembly is dependent on ATP concentration. Conceptually, this work identifies metazoan disaggregases challenging the widely accepted paradigm that the amyloid state is irreversible in mammalian cells. The data also provides alternative insights into pathogenic amyloids by examining their disassembly in cellular systems.