Analysis of novel hyperosmotic shock response suggests “beads in liquid” cytosol structure

Abstract

Proteins can aggregate in response to stresses, including hyperosmotic shock. Formation and disassembly of aggregates is a relatively slow process. We describe a novel instant response of the cell to hyperosmosis, during which chaperones and other proteins form numerous foci with properties uncharacteristic of classical aggregates. These foci appeared/disappeared seconds after shock onset/removal, in close correlation with cell volume changes. Genome-wide and targeted testing revealed chaperones, metabolic enzymes, P-body components and amyloidogenic proteins in the foci. Most of these proteins can form large assemblies and for some, the assembled state was pre-requisite for participation in foci. A genome-wide screen failed to identify genes whose absence prevented foci participation by Hsp70. Shapes of and interconnections between foci, revealed by super-resolution microscopy, indicated that the foci were compressed between other entities. Based on our findings, we suggest a new model of cytosol architecture as a collection of numerous gel-like regions suspended in a liquid network. This network is reduced in volume in response to hyperosmosis and forms small pockets between the gel-like regions.

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“…In addition to HOPS in mammalian cells, evidence is emerging that osmotic stress in other eukaryotes elicits a rapid phase-separation-like response. Notably, a similar response is observed in yeast, suggesting that the sensitivity of proteomes to osmotic changes may be an evolutionarily ancient adaptation and may point to a broader class of mechanisms that use phase separation to sense and rapidly respond to osmotic fluctuations ( 77 , 102 ).…”

A Crucial Role for the Protein Quality Control System in Motor Neuron Diseases

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