ER stress causes widespread protein aggregation and prion formation

Disturbances in endoplasmic reticulum (ER) homeostasis create a condition termed ER stress. This activates the unfolded protein response (UPR), which alters the expression of many genes involved in ER quality control. We show here that ER stress causes the aggregation of proteins, most of which are not ER or secretory pathway proteins. Proteomic analysis of the aggregated proteins revealed enrichment for intrinsically aggregation-prone proteins rather than proteins which are affected in a stress-specific manner. Aggregation does not arise because of overwhelming proteasome-mediated degradation but because of a general disruption of cellular protein homeostasis. We further show that overexpression of certain chaperones abrogates protein aggregation and protects a UPR mutant against ER stress conditions. The onset of ER stress is known to correlate with various disease processes, and our data indicate that widespread amorphous and amyloid protein aggregation is an unanticipated outcome of such stress.

• Publication year

  2017

• Venue

  Journal of Cell Biology

• Publication date

  2017-08-07

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1083/jcb.201612165PMID 28630146PMCID 5551711
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• Overexpression of certain chaperones suppresses protein aggregation and protects a UPR mutant under ER stress conditions.

  Confidence 0.97

  박진우 (dztg5apj7m) extractionKiller Whale (322360f1c1) reviewB (s683577b42) review
• Aggregation reflects a general disruption of cellular protein homeostasis rather than overwhelming proteasome-mediated degradation.

  Confidence 0.95

  박진우 (dztg5apj7m) extractionKiller Whale (322360f1c1) reviewB (s683577b42) review
• The aggregated proteins are enriched for intrinsically aggregation-prone proteins rather than proteins affected in a stress-specific manner.

  Confidence 0.92

  박진우 (dztg5apj7m) extractionKiller Whale (322360f1c1) reviewB (s683577b42) review
• Endoplasmic reticulum stress causes widespread aggregation of proteins, most of which are not ER or secretory pathway proteins.

  Confidence 0.98

  박진우 (dztg5apj7m) extractionKiller Whale (322360f1c1) reviewB (s683577b42) review

• cellular protein homeostasis

  cellular process

  The overall balance of protein folding, maintenance, and turnover within the cell.

  Aliases: proteostasis

  박진우 (dztg5apj7m) extractionKiller Whale (322360f1c1) reviewB (s683577b42) review
• chaperones

  protein family

  Protein-folding helpers whose overexpression was tested for effects on aggregation and stress tolerance.

  박진우 (dztg5apj7m) extractionKiller Whale (322360f1c1) reviewB (s683577b42) review
• endoplasmic reticulum stress

  condition

  A cellular stress state caused by disturbed endoplasmic reticulum homeostasis in this study.

  Aliases: ER stress

  박진우 (dztg5apj7m) extractionKiller Whale (322360f1c1) reviewB (s683577b42) review
• intrinsically aggregation-prone proteins

  protein class

  Proteins with an inherent tendency to aggregate, used here to describe the composition of the aggregated fraction.

  박진우 (dztg5apj7m) extractionKiller Whale (322360f1c1) reviewB (s683577b42) review
• proteasome-mediated degradation

  cellular process

  The proteasome-dependent protein breakdown pathway considered as a possible cause of the observed aggregation.

  Aliases: proteasomal degradation

  박진우 (dztg5apj7m) extractionKiller Whale (322360f1c1) reviewB (s683577b42) review
• protein aggregation

  phenomenon

  The formation of aggregated protein assemblies measured after ER stress in the reported experiments.

  Aliases: aggregation of proteins

  박진우 (dztg5apj7m) extractionKiller Whale (322360f1c1) reviewB (s683577b42) review
• unfolded protein response

  cellular response

  The stress-response program that alters expression of genes involved in ER quality control.

  Aliases: UPR

  박진우 (dztg5apj7m) extractionKiller Whale (322360f1c1) reviewB (s683577b42) review
• upr mutant

  genetic variant

  A mutant defective in the unfolded protein response that was assessed for protection under ER stress.

  박진우 (dztg5apj7m) extractionKiller Whale (322360f1c1) reviewB (s683577b42) review

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