Dictyostelium discoideum has a highly Q/N-rich proteome and shows an unusual resilience to protein aggregation

Abstract

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. molecular chaperones | proteostasis | Dictyostelium discoideum | protein aggregation | prion

Using the social amoeba Dictyostelium to study the functions of proteins linked to neuronal ceroid lipofuscinosis

“…Dictyostelium also contains the highest content of prion-like proteins of all organisms investigated to date [11, 12]. Intriguingly, prion-like proteins known to generate insoluble deposits in other eukaryotic cells, do not aggregate in Dictyostelium [11, 12].…”

“…Dictyostelium also contains the highest content of prion-like proteins of all organisms investigated to date [11, 12]. Intriguingly, prion-like proteins known to generate insoluble deposits in other eukaryotic cells, do not aggregate in Dictyostelium [11, 12]. Instead these proteins accumulate in the nucleus and are broken down by the ubiquitin–proteasome system suggesting that Dictyostelium has undergone specific adaptations that allow it to efficiently regulate its prion-like proteome [11, 12].…”

“…Intriguingly, prion-like proteins known to generate insoluble deposits in other eukaryotic cells, do not aggregate in Dictyostelium [11, 12]. Instead these proteins accumulate in the nucleus and are broken down by the ubiquitin–proteasome system suggesting that Dictyostelium has undergone specific adaptations that allow it to efficiently regulate its prion-like proteome [11, 12]. Thus, understanding the pathways involved in preventing protein aggregation in Dictyostelium could provide novel routes to tackling neurological disorders characterized by protein aggregation (e.g., Alzheimer’s, Parkinson’s, and Huntington’s disease).…”

CAMELOT: A machine learning approach for coarse-grained simulations of aggregation of block-copolymeric protein sequences

“…1, [18][19][20][21][22][23][24][25][26][27][28][29][30] The sequence blocks in these proteins are either well-folded domains or intrinsically disordered regions (IDRs). The latter refer to regions that fail to fold into unique three-dimensional structures as autonomous units.…”

Studying the Protein Quality Control System of <em>D. discoideum</em> Using Temperature-controlled Live Cell Imaging

“…Recently, we established D. discoideum as a new system to study the protein quality control (PQC) system 6,7 . Its proteome is enriched in aggregation-prone prion-like proteins, which poses a challenge to protein quality control 8 .…”