Protein Phase Separation as a Stress Survival Strategy

Abstract

Cells under stress must adjust their physiology, metabolism, and architecture to adapt to the new conditions. Most importantly, they must down-regulate general gene expression, but at the same time induce synthesis of stress-protective factors, such as molecular chaperones. Here, we investigate how the process of phase separation is used by cells to ensure adaptation to stress. We summarize recent findings and propose that the solubility of important translation factors is specifically affected by changes in physical-chemical parameters such temperature or pH and modulated by intrinsically disordered prion-like domains. These stresstriggered changes in protein solubility induce phase separation into condensates that regulate the activity of the translation factors and promote cellular fitness. Prion-like domains play important roles in this process as environmentally regulated stress sensors and modifier sequences that determine protein solubility and phase behavior. We propose that protein phase separation is an evolutionary conserved feature of proteins that cells harness to regulate adaptive stress responses and ensure survival in extreme environmental conditions.

A widespread family of heat-resistant obscure (Hero) proteins protect against protein instability and aggregation

“…This client-protective action of Hero proteins is seemingly opposite to the common notion of IDPs/IDRs as autonomous aggregation inducers. Notably, however, it was recently proposed that a prion-like IDR in yeast Sup35 acts to protect Sup35 itself against proteotoxic damage, by extending its soluble/reversible phase space and thereby preventing it from irreversible aggregation (Franzmann and Alberti, 2019;Franzmann et al, 2018). Thus, it is tempting to speculate that Hero proteins can impart at least a part of their protective functions in a similar manner as the prion-like IDR in Sup35, except that they do so in trans on their client proteins.…”

Alphavirus nsP3 ADP-ribosylhydrolase Activity Disrupts Stress Granule Formation

“…Yet, G3BP1/2 and its association with the nsP3 HVD are required for CHIKV replication [40,62]. We note, however, that the HVD is composed of low-complexity regions [39], which are increasingly appreciated for their role in mediating the assembly of non-membranous structures [6][7][8]. Here, we instead propose a model of how nsP3 mediates SG disassembly, wherein the C-terminal HVD promotes the association between nsP3 and SG proteins so that the N-terminal MD can act locally to remove ADP-ribosylation in SGs.…”

“…The sudden influx of untranslated mRNAs is proposed to seed the formation of SGs, where the polynucleotide promotes local concentration of proteins through non-covalent binding [5]. These RNA-binding proteins are highly enriched with low-complexity regions, and emergent data indicate that the nonspecific, weak interactions between these regions are responsible for the condensation of proteins to form higherorder structures, such as microscopically visible SGs [6][7][8]. Depending on the type of stress, the composition of SGs could vary [9], but certain common components, such as Ras GTP-activating protein-binding proteins G3BP1/2, are essential for SG formation [10,11].…”

Protein phase separation and determinants of in cell crystallization

“…In cellulo MLOs are formed by LLPS. They lack a lipid boundary, can contain different types of biomolecules, have specific functions and ensure that distinct cellular functions occur in a spatiotemporally controlled manner . However, our knowledge and understanding of the dynamic assembly, partitioning of molecules and reaction kinetics of MLOs and corresponding LLPS is still limited.…”