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A Concentration-Dependent Liquid Phase Separation Can Cause Toxicity upon Increased Protein Expression.

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Cellular toxicity can arise from proteins forming liquid droplets, not just solid aggregates. This concentration-dependent liquid-liquid demixing impacts cell function and disease.

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Area of Science:

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Background:

  • Human diseases are linked to protein aggregation, a liquid-to-solid phase transition.
  • Amyloid fibers and protein aggregates are hallmarks of various pathological conditions.

Purpose of the Study:

  • To investigate an alternative mechanism of cellular toxicity: concentration-dependent liquid-liquid demixing.
  • To explore the role of liquid phase separation in protein dosage sensitivity and disease.

Main Methods:

  • Analysis of yeast proteins that exhibit toxicity upon increased concentration.
  • Characterization of physicochemical properties of toxic proteins.
  • Induction and observation of cytoplasmic foci formation.
  • Assessment of focus reversibility and impact on cell growth.
  • Intervention to prevent demixing and evaluate protein dosage sensitivity.

Main Results:

  • Proteins toxic at high concentrations share properties with those involved in physiological liquid-liquid demixing.
  • Increased concentration of these proteins leads to the formation of liquid cytoplasmic foci.
  • Demixing coincides with the onset of toxicity, sequestering proteins and mRNAs.
  • Focus dissolution and protein concentration decrease correlate with growth recovery.
  • Inhibition of demixing prevents protein dosage sensitivity.

Conclusions:

  • Inappropriate liquid phase separation is a potential cause of protein dosage sensitivity.
  • Triggering aberrant liquid demixing may contribute to the development of human diseases.
  • This mechanism offers a new perspective on cellular toxicity beyond traditional protein aggregation.