Fibril-induced glutamine-/asparagine-rich prions recruit stress granule proteins in mammalian cells

Abstract

Prions of lower eukaryotes are self-templating protein aggregates that replicate by converting homotypic proteins into stable, tightly packed beta-sheet–rich protein assemblies. Propagation is mediated by prion domains, low-complexity regions enriched in polar and devoid of charged amino acid residues. In mammals, compositionally similar domains modulate the assembly of dynamic stress granules (SGs) that associate via multivalent weak interactions. Dysregulation of SGs composed of proteins with prion-like domains has been proposed to underlie the formation of pathological inclusions in several neurodegenerative diseases. The events that drive prion-like domains into transient or solid assemblies are not well understood. We studied the interactors of the prototype prion domain NM of Saccharomyces cerevisiae Sup35 in its soluble or fibril-induced prion conformation in the mammalian cytosol. We show that the interactomes of soluble and prionized NM overlap with that of SGs. Prion induction by exogenous seeds does not cause SG assembly, demonstrating that colocalization of aberrant protein inclusions with SG components does not necessarily reveal SGs as initial sites of protein misfolding.

Functional Mammalian Amyloids and Amyloid-Like Proteins

“…Notably, Sup35 PrD can substitute for the TIA-1 PrDL domain in the process of SG nucleation in mammalian cells [ 219 ]. Additionally, Sup35 PrD fused to hemagglutinin tag is recruited into SGs in non-stressed cells of the N2a cell line [ 220 ]. Rayman and Kandel reported a transition of TIA-1 from the monomeric state into an SDS-resistant (possibly amyloid-like) structure in a mouse brain [ 221 ].…”

RNA-binding and prion domains: the Yin and Yang of phase separation

“…IDRs often contain weak adhesive elements (high stickiness or reactivity to bind) that allow interaction with multiple partners (or promiscuity), including the molecule itself ( 24–26 ). This property is the hallmark of Prion Like Domains (PrLD) that favour nucleation of large macromolecular assemblies ( 27–31 ).…”

RNA-Binding and Prion Domains: The Yin and Yang of Phase Separation

“…The IDRs can contain weak adhesive elements (high stickiness / reactivity to bind) that allow the interaction with multiple partners (promiscuity), including the molecule itself 24,25 . This property is the hallmark of Prion Like Domains (PrLD) that are able to favour nucleation of large macromolecular assemblies 26,27,28,29,30 . Also RNA molecules have been also reported to modulate the dynamicity 31,32 and the phase separation process of biomolecular condensates 33,34,35,36 .…”