title: Metazoan Hsp70 machines use Hsp110 to power protein disaggregation.
abstract: Accumulation of aggregation-prone misfolded proteins disrupts normal cellular function and promotes ageing and disease. Bacteria, fungi and plants counteract this by solubilizing and refolding aggregated proteins via a powerful cytosolic ATP-dependent bichaperone system, comprising the AAA+ disaggregase Hsp100 and the Hsp70-Hsp40 system. Metazoa, however, lack Hsp100 disaggregases. We show that instead the Hsp110 member of the Hsp70 superfamily remodels the human Hsp70-Hsp40 system to efficiently disaggregate and refold aggregates of heat and chemically denatured proteins in vitro and in cell extracts. This Hsp110 effect relies on nucleotide exchange, not on ATPase activity, implying ATP-driven chaperoning is not required. Knock-down of nematode Caenorhabditis elegans Hsp110, but not an unrelated nucleotide exchange factor, compromises dissolution of heat-induced protein aggregates and severely shortens lifespan after heat shock. We conclude that in metazoa, Hsp70-Hsp40 powered by Hsp110 nucleotide exchange represents the crucial disaggregation machinery that reestablishes protein homeostasis to counteract protein unfolding stress.
authors.affiliation: Center for Molecular Biology of the University of Heidelberg and German Cancer Research Center, DKFZ-ZMBH Alliance, Heidelberg, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Rampelt
authors.forename: Janine
authors.initials: J
authors.lastname: Kirstein-Miles
authors.forename: Nadinath B
authors.initials: NB
authors.lastname: Nillegoda
authors.forename: Kang
authors.initials: K
authors.lastname: Chi
authors.forename: Sebastian R
authors.initials: SR
authors.lastname: Scholz
authors.forename: Richard I
authors.initials: RI
authors.lastname: Morimoto
authors.forename: Bernd
authors.initials: B
authors.lastname: Bukau
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017173:Caenorhabditis elegans / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D049452:Green Fluorescent Proteins / Q000378:metabolism; D050957:HSP110 Heat-Shock Proteins / Q000378:metabolism*; D050956:HSP40 Heat-Shock Proteins / Q000378:metabolism*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D018869:Heat-Shock Response / Q000502:physiology; D006801:Humans; D006868:Hydrolysis; D002479:Inclusion Bodies; D008156:Luciferases / Q000378:metabolism*; D011489:Protein Denaturation; D055503:Protein Multimerization; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism
chemical_list: D050957:HSP110 Heat-Shock Proteins; D050956:HSP40 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; D029701:Saccharomyces cerevisiae Proteins; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D000255:Adenosine Triphosphate; D008156:Luciferases