Feedback control of prion formation and propagation by the ribosome‐associated chaperone complex

Summary Cross‐beta fibrous protein aggregates (amyloids and amyloid‐based prions) are found in mammals (including humans) and fungi (including yeast), and are associated with both diseases and heritable traits. The H sp104/70/40 chaperone machinery controls propagation of yeast prions. The H sp70 chaperones S sa and S sb show opposite effects on [ PSI + ], a prion form of the translation termination factor S up35 (e RF 3). S sb is bound to translating ribosomes via ribosome‐associated complex ( RAC ), composed of H sp40‐ Z uo1 and H sp70‐ S sz1. Here we demonstrate that RAC disruption increases de novo prion formation in a manner similar to S sb depletion, but interferes with prion propagation in a manner similar to S sb overproduction. Release of S sb into the cytosol in RAC ‐deficient cells antagonizes binding of S sa to amyloids. Thus, propagation of an amyloid formed because of lack of ribosome‐associated S sb can be counteracted by cytosolic S sb, generating a feedback regulatory circuit. Release of S sb from ribosomes is also observed in wild‐type cells during growth in poor synthetic medium. Ssb is, in a significant part, responsible for the prion destabilization in these conditions, underlining the physiological relevance of the S sb‐based regulatory circuit.