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DARKSIDE Report Summary

Project ID: 337713
Funded under: FP7-IDEAS-ERC
Country: Israel

Mid-Term Report Summary - DARKSIDE (Harnessing the Dark Side of Protein Folding: Manipulating Aggregation for Recombinant Protein Production)

Cytoplasmic re-organization in response to stress conditions is essential for effective cellular stress response. Translational machinery is packaged into transient RNP granules, many biosynthetic enzymes are sequestered in storage granules, and misfolded proteins accumulate in dynamic inclusions with a diverse set of functions. All such compartments are not bound by membranes, and instead are thought to phase-separate into liquid-like droplets from free cytoplasm via low complexity hydrophobic promiscuous interactions. Under prolonged stress or energy depletion these droplets can progress towards insolubility and aggregation. This tendency of liquid-like cytoplasmic droplets to mature to solid phase structures translates into the pathological phenomenon of protein aggregation, and is highly relevant to understanding the onset of neurodegenerative diseases and the process of cellular aging. Our previous work suggests that this process is tightly regulated in the cell, but it is not clear how this regulation takes place.
Our progress in the DarkSide ERC project has so far uncovered a novel mechanism for aggregate solubilization, and for active aggregation. These findings significantly improve our understanding of how cells regulate protein biogenesis in response to stress. In data that are not yet published, we have also discovered a novel way for communicating cell stress from the cellular membrane to the cytoplasm. Additionally, we have shown that the regulation of aggregate solubility can have a profound impact on the duration and recovery from acute stress.

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