Similarities of stress granules and cytosolic prions

Abstract

Eukaryotic cells contain several organelles that lack a delimiting membrane. These membrane-less organelles take over important functions within the cell and influence biological reactions by condensing nucleic acids and proteins into dense droplets. Upon environmental stress, one kind of membrane-less organelle, termed stress granules, assembles to sequester non-essential mRNA transcripts while translation is stalled. Together with RNA-binding proteins, mRNA transcripts form a network by multiple weak interactions within stress granules. Many RNA-binding proteins thereby facilitate the assembly of stress granules by their low-complexity or prion-like domains, which were identified based on their structural similarities with yeast prion domains. Several RNA-binding proteins that are part of stress granules were found aggregated in degenerative disorders. Therefore, stress granules have been proposed to contribute to the disease process by acting as nucleation sites for protein aggregates, which might evolve into pathological protein inclusions over time. In this study, we compared similarities and differences between stress granules and cytosolic prion aggregates. Specifically, we tested the hypothesis if recruitment of a protein with a prion-like domain to stress granules induces its conversion into a protein aggregate with self-perpetuating properties. To this end, we made use of the yeast prion domain NM of Sup35, expressed in mammalian cells, that can form cytosolic prions upon exposure to recombinant NM fibrils. Here we show that the interactome of NM prions significantly overlaps with that of stress granules. The presence of neither soluble nor aggregated NM altered the dynamics of stress granules, but stress granule disassembly was slightly impaired. Importantly, prolonged presence of stress granules did not induce NM aggregation, but rather led to cell death. Interestingly, chemicals that induce stress granules drastically increased NM aggregate formation upon concomitant induction with recombinant NM fibrils. However, stress granules per se were not required for the increased induction rate, as concomitant exposure to drugs or siRNA that interfere with stress granule formation did not lower the NM aggregate induction rates. We propose a model where stress that triggers a stress granule response results in a cellular environment that allows more effective protein aggregate induction by exogenous seeds. One possible explanation for this is that the cellular quality control mechanism is overloaded under stress and thus cannot combat the additional aggregate induction by an exogenous seed. Therefore, the role of stress granules in the pathogenesis of neurodegenerative disorders might be different than so far anticipated. Still, triggers that cause stress granule formation enhance protein aggregation in the presence of exogenous seeds, thereby likely contributing to disease progression.