Alcohol exposure induces reversible nucleolar amyloidogenesis

Abstract

The nucleolus is a dynamic membraneless organelle that rapidly responds to cellular perturbations. Under harsh environmental conditions, it transitions from a ribosome biogenesis center into a dense proteinaceous structure, known as a nucleolar amyloid body (A-body). Although A-bodies share biophysical characteristics with pathological amyloids, these physiological structures are non-toxic, protective, and reversible. Here, we identify alcohol exposure as an A-body-inducing stimulus. Our findings demonstrate that cells remain viable during alcohol treatment and that ethanol-induced A-bodies are reversible upon restoration of physiological conditions. These structures form through a signaling pathway distinct from previously characterized stimuli, yet still require the proto-oncogene c-Myc and regulatory noncoding RNAs to drive nucleolar remodeling. Ethanol also induces a distinct A-body proteome, allowing us to investigate how protein structure governs selective susceptibility to different denaturing environments. Using homologous RNA helicases, we demonstrate that single amino acid substitutions can dramatically alter stress-dependent protein destabilization and recruitment to A-bodies. Similarly, disease-associated protein variants display altered aggregation behavior relative to their wild-type counterparts. Together, this work establishes alcohol exposure as a physiological trigger of reversible nucleolar amyloid formation and provides insight into how protein structure may have evolved to influence susceptibility to stress-induced misfolding.