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

Massimo Ganassi; Daniel Mateju; Ilaria Bigi; Laura Mediani; Ina Poser; Hyun O Lee; Samuel J Seguin; Federica F Morelli; Jonathan Vinet; Giuseppina Leo; Orietta Pansarasa; Cristina Cereda; Angelo Poletti; Simon Alberti; Serena Carra

doi:10.1016/j.molcel.2016.07.021

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.

Authors

Affiliations

¹ Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena 41125, Italy.
² Max Planck Institute of Molecular Cell Biology and Genetics, Dresden 01307, Germany.
³ Laboratory of Experimental Neurobiology, "C. Mondino" National Institute of Neurology Foundation, IRCCS, Via Mondino 2, 27100 Pavia, Italy.
⁴ Department of Pharmacological and Biomolecular Sciences, Centre of Excellence on Neurodegenerative Diseases University of Milan, Milan 20133, Italy.
⁵ Max Planck Institute of Molecular Cell Biology and Genetics, Dresden 01307, Germany. Electronic address: [email protected].
⁶ Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena 41125, Italy. Electronic address: [email protected].

PMID: 27570075
DOI: 10.1016/j.molcel.2016.07.021

Abstract

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*

Substances

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