Hsp70-Bag3 complex is a hub for proteotoxicity-induced signaling that controls protein aggregation

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Extraction and Visualization of Protein Aggregates after Treatment of Escherichia coli with a Proteotoxic Stressor
07:59

Extraction and Visualization of Protein Aggregates after Treatment of Escherichia coli with a Proteotoxic Stressor

Published on: June 29, 2021

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Anatoli B Meriin1, Arjun Narayanan2, Le Meng1

  • 1Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118.

Proceedings of the National Academy of Sciences of the United States of America
|July 11, 2018
PubMed

Insights

Cells sense toxic protein buildup using the Hsp70-Bag3 complex, which detects stalled polypeptides and regulates early-stage protein aggregation to maintain cell health.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Protein Homeostasis

Background:

  • Cellular pathologies often stem from protein abnormalities and misfolded polypeptides.
  • Cells possess adaptive responses to mitigate the toxicity of aberrant proteins.
  • The sensing mechanism for protein buildup, often linked to proteasome failure, remains poorly understood.

Purpose of the Study:

  • To elucidate the mechanism by which cells detect the accumulation of misfolded proteins.
  • To identify the key molecular players involved in sensing proteotoxicity.
  • To understand how this sensing mechanism regulates cellular responses, including protein aggregation.

Main Methods:

  • Investigated the role of the heat shock protein 70-Bcl-2-associated athanogene 3 (Hsp70-Bag3) complex in response to proteasome suppression.
  • Utilized components of the ribosome quality control system (LTN1, VCP) and ribosome-associated chaperone NAC.
  • Analyzed the regulation of signaling pathways, including the Hippo pathway (LATS1/2) and stress kinases (p38, JNK).
  • Monitored the emergence and growth of abnormal protein oligomers under proteotoxic stress.

Main Results:

  • The Hsp70-Bag3 complex acts as a crucial sensor for defective ribosomal products, particularly stalled polypeptides, upon proteasome suppression.
  • Interaction with the Hsp70-Bag3 complex requires LTN1, VCP, and NAC.
  • This complex modulates the Hippo pathway effectors LATS1/2 and stress kinases p38 and JNK.
  • Hsp70-Bag3-LATS1/2 signaling under proteotoxic stress regulates the early stages of protein aggregation, controlling the emergence and growth of small oligomers.

Conclusions:

  • The Hsp70-Bag3 complex is a key signaling node that senses proteotoxicity.
  • This complex triggers multiple cellular pathways, including those controlling protein aggregation at its earliest stages.
  • Understanding this mechanism provides insights into cellular defense against protein misfolding pathologies.
Keywords:
DRiPsHippo pathwayaggresomeproteasome inhibitionstress kinases

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