Human J-protein DnaJB6b Cures a Subset of Saccharomyces cerevisiae Prions and Selectively Blocks Assembly of Structurally Related Amyloids

Human chaperone DnaJB6, an Hsp70 co-chaperone whose defects cause myopathies, protects cells from polyglutamine toxicity and prevents purified polyglutamine and A peptides from forming amyloid. Yeast prions [URE3] and [PSI+] propagate as amyloid forms of Ure2 and Sup35 proteins, respectively. Here we find DnaJB6-protected yeast cells from polyglutamine toxicity and cured yeast of both [URE3] prions and weak variants of [PSI+] prions but not strong [PSI+] prions. Weak and strong variants of [PSI+] differ only in the structural conformation of their amyloid cores. In line with its anti-prion effects, DnaJB6 prevented purified Sup35NM from forming amyloids at 37 degrees C, which produce predominantly weak [PSI+] variants when used to infect yeast, but not at 4 degrees C, which produces mostly strong [PSI+] variants. Thus, structurally distinct amyloids composed of the same protein were differentially sensitive to the anti-amyloid activity of DnaJB6 both in vitro and in vivo. These findings have important implications for strategies using DnaJB6 as a target for therapy in amyloid disorders.