Many
protein-misfolding diseases are caused by
proteins carrying
prion-like domains. These
proteins show sequence similarity to yeast
prion proteins, which can interconvert between an intrinsically disordered and an aggregated
prion state. The natural presence of
prions in yeast has provided important insight into disease mechanisms and cellular proteostasis. However, little is known about
prions in other organisms, and it is not yet clear whether the findings in yeast can be generalized. Using bioinformatics tools, we show that Dictyostelium discoideum has the highest content of
prion-like
proteins of all organisms investigated to date, suggesting that its
proteome has a high overall aggregation propensity. To study mechanisms regulating these
proteins, we analyze the behavior of several well-characterized
prion-like
proteins, such as an expanded version of human huntingtin exon 1 (Q103) and the
prion domain of the yeast
prion protein Sup35 (NM), in D. discoideum. We find that these
proteins remain soluble and are innocuous to D. discoideum, in contrast to other organisms, where they form cytotoxic cytosolic aggregates. However, when exposed to conditions that compromise
molecular chaperones, these
proteins aggregate and become cytotoxic. We show that the disaggregase Hsp101, a
molecular chaperone of the Hsp100 family, dissolves heat-induced aggregates and promotes thermotolerance. Furthermore,
prion-like
proteins accumulate in the nucleus, where they are targeted by the
ubiquitin-
proteasome system. Our data suggest that D. discoideum has undergone specific adaptations that increase the proteostatic capacity of this organism and allow for an efficient regulation of its
prion-like
proteome.