The story of stolen chaperones

Abstract

Prions are self-seeding alternate protein conformations. Most yeast prions contain glutamine/asparagine (Q/N)-rich domains that promote the formation of amyloid-like prion aggregates. Chaperones, including Hsp104 and Sis1, are required to continually break these aggregates into smaller “seeds.” Decreasing aggregate size and increasing the number of growing aggregate ends facilitates both aggregate transmission and growth. Our previous work showed that overexpression of 11 proteins with Q/N-rich domains facilitates the de novo aggregation of Sup35 into the [PSI+] prion, presumably by a cross-seeding mechanism. We now discuss our recent paper, in which we showed that overexpression of most of these same 11 Q/N-rich proteins, including Pin4C and Cyc8, destabilized pre-existing Q/N rich prions. Overexpression of both Pin4C and Cyc8 caused [PSI+] aggregates to enlarge. This is incompatible with a previously proposed “capping” model where the overexpressed Q/N-rich protein poisons, or “caps,” the growing aggregate ends. Rather the data match what is expected of a reduction in prion severing by chaperones. Indeed, while Pin4C overexpression does not alter chaperone levels, Pin4C aggregates sequester chaperones away from the prion aggregates. Cyc8 overexpression cures [PSI+] by inducing an increase in Hsp104 levels, as excess Hsp104 binds to [PSI+] aggregates in a way that blocks their shearing.

Prion-like domains as epigenetic regulators, scaffolds for subcellular organization, and drivers of neurodegenerative disease

“…Hsp70 and Hsp40 chaperones often get sequestered and inactivated by misfolded protein aggregates (Auluck et al, 2002; Derkatch and Liebman, 2013; Yu et al, 2014). Thus, enhancement or engineering of this disaggregase machinery might also open potential therapeutic avenues for ALS, FTD, and a variety of other neurodegenerative disorders.…”

“…In metazoan cells and yeast, the Hsp110, Hsp70, and Hsp40 protein-disaggregase machinery ( Nillegoda and Bukau, 2015 ; Shorter, 2011 ; Torrente and Shorter, 2013 ), contributes to the clearance of stress granules ( Cherkasov et al, 2013 ; Kroschwald et al, 2015 ; Walters et al, 2015 ). Hsp70 and Hsp40 chaperones often get sequestered and inactivated by misfolded protein aggregates ( Auluck et al, 2002 ; Derkatch and Liebman, 2013 ; Yu et al, 2014 ). Thus, enhancement or engineering of this disaggregase machinery might also open potential therapeutic avenues for ALS, FTD, and a variety of other neurodegenerative disorders.…”

Heterologous Aggregates Promote De Novo Prion Appearance via More than One Mechanism

“…The titration model postulates that cellular factors responsible for the disassembly of aggregates and the refolding of misfolded proteins are so busy working on the existing [ PIN + ] prion that they are not available to prevent the appearance of the new prion, [ PSI + ] [22] , [51] , [65] . In support of this model, prion-like aggregates have been shown to colocalize with chaperones, reducing the cytosolic level of chaperones and thereby affecting the stability of heterologous prion aggregates in the cell [66] – [70] .…”

Microbiome-Derived Prion-Like Proteins and Their Potential to Trigger Cognitive Dysfunction

“…The intensity of red in the E. coli colonies is linked with the capacity of the extracellular aggregates to bind CR. The ring structures are precursors of foci and their impaired fragmentation is associated with the accumulation of elongated structures and poorer propagation 65,67,80 . Similarly, an increase in gut granules fluorescence has been associated with enhanced activity of these organelles 79 .…”