A Surveillance Function of the HSPB8-BAG3-HSP70 Chaperone Complex Ensures Stress Granule Integrity and Dynamism

Mol Cell. 2016 Sep 1;63(5):796-810. doi: 10.1016/j.molcel.2016.07.021. Epub 2016 Aug 25.


Stress granules (SGs) are ribonucleoprotein complexes induced by stress. They sequester mRNAs and disassemble when the stress subsides, allowing translation restoration. In amyotrophic lateral sclerosis (ALS), aberrant SGs cannot disassemble and therefore accumulate and are degraded by autophagy. However, the molecular events causing aberrant SG formation and the molecular players regulating this transition are largely unknown. We report that defective ribosomal products (DRiPs) accumulate in SGs and promote a transition into an aberrant state that renders SGs resistant to RNase. We show that only a minor fraction of aberrant SGs is targeted by autophagy, whereas the majority disassembles in a process that requires assistance by the HSPB8-BAG3-HSP70 chaperone complex. We further demonstrate that HSPB8-BAG3-HSP70 ensures the functionality of SGs and restores proteostasis by targeting DRiPs for degradation. We propose a system of chaperone-mediated SG surveillance, or granulostasis, which regulates SG composition and dynamics and thus may play an important role in ALS.

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism*
  • Arsenites / pharmacology
  • Autophagy / genetics*
  • Cytoplasmic Granules / chemistry
  • Cytoplasmic Granules / drug effects
  • Cytoplasmic Granules / metabolism*
  • Gene Expression
  • HSP70 Heat-Shock Proteins / genetics
  • HSP70 Heat-Shock Proteins / metabolism*
  • HeLa Cells
  • Heat-Shock Proteins / genetics
  • Heat-Shock Proteins / metabolism*
  • Homeostasis
  • Humans
  • Leupeptins / pharmacology
  • Molecular Chaperones
  • Oxidative Stress
  • Proteasome Inhibitors / pharmacology
  • Protein Binding
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • Proteolysis
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Ribonucleases / metabolism
  • Ribosomes / genetics
  • Ribosomes / metabolism*


  • Adaptor Proteins, Signal Transducing
  • Apoptosis Regulatory Proteins
  • Arsenites
  • BAG3 protein, human
  • HSP70 Heat-Shock Proteins
  • HSPB8 protein, human
  • Heat-Shock Proteins
  • Leupeptins
  • Molecular Chaperones
  • Proteasome Inhibitors
  • RNA, Messenger
  • Protein Serine-Threonine Kinases
  • Ribonucleases
  • arsenite
  • benzyloxycarbonylleucyl-leucyl-leucine aldehyde