Adaptation to Stressors by Systemic Protein Amyloidogenesis

Abstract

Summary The amyloid state of protein organization is typically associated with debilitating human neuropathies and 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.

In vivo vizualisation of mono-ADP-ribosylation by dPARP16 upon amino-acid starvation

“…The discovery of a short peptide required for the formation of Sec bodies is reminiscent to the existence of an Amyloid Converting Peptide in proteins found in nuclear amyloid bodies in cells upon several stress (Audas et al, 2016). Interestingly, amyloidogenesis is mediated by this motif binding a long non-coding RNA that could be equivalent or comparable to the SRDC MARylation during Sec body formation.…”

Profilin reduces aggregation and phase separation of huntingtin N-terminal fragments by preferentially binding to soluble monomers and oligomers

“…Phase separation refers to aggregation-related changes in molecular density that give rise to the coexistence of dilute macromolecule-deficient phases and dense macromolecule-rich phases (3,14,15). Examples of multiple coexisting phases have been observed in biological contexts (15)(16)(17)(18), and these phases can be liquid, solid, or semisolid (e.g., a gel) (10,(19)(20)(21)(22)(23)(24)(25). Driving forces for phase separation are quantified in terms of saturation concentrations (14,19,26).…”

RNA-Seeded Functional Amyloids Balance Growth and Survival

“…Remarkably, Audas et al (2016) find that ABs form through a liquid-to-solid transition mediated by amyloid formation. Amyloids are best known as self-assembled aberrant protein aggregates that are associated with amyloidosis and debilitating neurodegenerative diseases such as Huntington’s, Alzheimer’s, and Parkinson’s diseases.…”

“… In this issue of Developmental Cell , Audas et al (2016) report non-membrane-enclosed amyloid bodies (ABs) assembled in the nuclei of cells exposed to heat and low pH. Remarkably, ABs form not by liquid-to-liquid phase separation, implicated in RNA-seeded granule assembly, but by an amyloidogenic process that promotes a liquid-to-solid transition.…”

“…Other RNA-seeded bodies include paraspeckles, processing (P)-bodies, germ cell granules, the histone locus, and cajal bodies (Courchaine et al, 2016). Reporting in this issue of Developmental Cell , Audas et al (2016) present evidence for a new RNA-seeded body that they call the amyloid body (AB) (Figure 1). ABs are nuclear foci that form in response to specific stresses.…”