Adaptation to Stressors by Systemic Protein Amyloidogenesis

The amyloid state of protein organization is typically associated with debilitating human neuropathies and is seldom observed in physiology. Here, we uncover a systemic program that leverages the amyloidogenic propensity of proteins to regulate cell adaptation to stressors. On stimulus, cells assemble the amyloid bodies (A-bodies), nuclear foci containing heterogeneous proteins with amyloid-like biophysical properties. A discrete peptidic sequence, termed the amyloid-converting motif (ACM), is capable of targeting proteins to the A-bodies by interacting with ribosomal intergenic noncoding RNA (rIGSRNA). The pathological β-amyloid peptide, involved in Alzheimer's disease, displays ACM-like activity and undergoes stimuli-mediated amyloidogenesis in vivo. Upon signal termination, elements of the heat-shock chaperone pathway disaggregate the A-bodies. Physiological amyloidogenesis enables cells to store large quantities of proteins and enter a dormant state in response to stressors. We suggest that cells have evolved a post-translational pathway that rapidly and reversibly converts native-fold proteins to an amyloid-like solid phase. [Display omitted] •Nuclear amyloid bodies (A-bodies) form from systemic protein amyloidogenesis•An amyloid-converting motif and ribosomal intergenic lncRNA mediate amyloidogenesis•The heat-shock chaperone pathway disaggregates A-bodies•Upon stimuli, cells activate physiological amyloidogenesis to enter a dormant state Audas et al. find that to adapt to stressors, heterogeneous proteins convert to an amyloid-like state and form subnuclear amyloid bodies (A-bodies), which requires a specific protein motif and ribosomal intergenic lncRNA. Upon stimuli termination, Hsp chaperones disaggregate A-bodies. This pathway regulates reversible amyloidogenesis of the Alzheimer’s disease-associated pathological β-amyloid peptide.