title: HspB8 participates in protein quality control by a non-chaperone-like mechanism that requires eIF2{alpha} phosphorylation.
abstract: Aggregation of mutated proteins is a hallmark of many neurodegenerative disorders, including Huntington disease. We previously reported that overexpression of the HspB8.Bag3 chaperone complex suppresses mutated huntingtin aggregation via autophagy. Classically, HspB proteins are thought to act as ATP-independent molecular chaperones that can bind unfolded proteins and facilitate their processing via the help of ATP-dependent chaperones such as the Hsp70 machine, in which Bag3 may act as a molecular link between HspB, Hsp70, and the ubiquitin ligases. However, here we show that HspB8 and Bag3 act in a non-canonical manner unrelated to the classical chaperone model. Rather, HspB8 and Bag3 induce the phosphorylation of the alpha-subunit of the translation initiator factor eIF2, which in turn causes a translational shut-down and stimulates autophagy. This function of HspB8.Bag3 does not require Hsp70 and also targets fully folded substrates. HspB8.Bag3 activity was independent of the endoplasmic reticulum (ER) stress kinase PERK, demonstrating that its action is unrelated to ER stress and suggesting that it activates stress-mediated translational arrest and autophagy through a novel pathway.
authors.affiliation: Department of Radiation and Stress Cell Biology, University Medical Center Groningen, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands. s.carra@med.umcg.nl
authors.forename: Serena
authors.initials: S
authors.lastname: Carra
authors.forename: Jeanette F
authors.initials: JF
authors.lastname: Brunsting
authors.forename: Herman
authors.initials: H
authors.lastname: Lambert
authors.forename: Jacques
authors.initials: J
authors.lastname: Landry
authors.forename: Harm H
authors.initials: HH
authors.lastname: Kampinga
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001343:Autophagy; D000071187:Autophagy-Related Protein 5; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000071058:Huntingtin Protein; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000502:physiology; D018832:Molecular Chaperones; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D014176:Protein Biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D020871:RNA Stability; D011994:Recombinant Proteins / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism; D018911:Trinucleotide Repeats; D019892:eIF-2 Kinase / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D000071187:Autophagy-Related Protein 5; D015852:Eukaryotic Initiation Factor-2; D006360:Heat-Shock Proteins; D000071058:Huntingtin Protein; D008869:Microtubule-Associated Proteins; D018832:Molecular Chaperones; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D011994:Recombinant Proteins; D019892:eIF-2 Kinase; C495773:Atg5 protein, mouse; C414431:BAG3 protein, human; C413214:HSPB8 protein, human; C086055:HTT protein, human; C070634:Eif2ak4 protein, mouse