A Non-amyloid Prion Particle that Activates a Heritable Gene Expression Program

Spatiotemporal gene regulation is often driven by RNA-binding proteins that harbor long intrinsically disordered regions in addition to folded RNA-binding domains. We report that the disordered region of the evolutionarily ancient developmental regulator Vts1/Smaug drives self-assembly into gel-like condensates. These proteinaceous particles are not composed of amyloid, yet they are infectious, allowing them to act as a protein-based epigenetic element: a prion [SMAUG+]. In contrast to many amyloid prions, condensation of Vts1 enhances its function in mRNA decay, and its self-assembly properties are conserved over large evolutionary distances. Yeast cells harboring [SMAUG+] downregulate a coherent network of mRNAs and exhibit improved growth under nutrient limitation. Vts1 condensates formed from purified protein can transform naive cells to acquire [SMAUG+]. Our data establish that non-amyloid self-assembly of RNA-binding proteins can drive a form of epigenetics beyond the chromosome, instilling adaptive gene expression programs that are heritable over long biological timescales. [Display omitted] •The Vts1 IDR promotes its condensation into the non-amyloid prion [SMAUG+]•[SMAUG+] hyperactivates Vts1 function•[SMAUG+] rewires post-transcriptional gene regulation to promote proliferation•Self-assembly is conserved in the human Vts1 homolog hSmaug1 Chakravarty et al. define a new mechanism in protein-based epigenetics. Self-assembly of the evolutionarily ancient RNA-binding protein Vts1/Smaug drives formation of a non-amyloid prion, [SMAUG+], that heritably activates protein function. [SMAUG+] rewires post-transcriptional gene expression landscapes to favor robust mitotic growth. Its self-assembly properties are conserved across eukaryotes.