title: Identification of the Drosophila ortholog of HSPB8: implication of HSPB8 loss of function in protein folding diseases.
abstract: Protein aggregation is a hallmark of many neuronal disorders, including the polyglutamine disorder spinocerebellar ataxia 3 and peripheral neuropathies associated with the K141E and K141N mutations in the small heat shock protein HSPB8. In cells, HSPB8 cooperates with BAG3 to stimulate autophagy in an eIF2α-dependent manner and facilitates the clearance of aggregate-prone proteins (Carra, S., Seguin, S. J., Lambert, H., and Landry, J. (2008) J. Biol. Chem. 283, 1437-1444; Carra, S., Brunsting, J. F., Lambert, H., Landry, J., and Kampinga, H. H. (2009) J. Biol. Chem. 284, 5523-5532). Here, we first identified Drosophila melanogaster HSP67Bc (Dm-HSP67Bc) as the closest functional ortholog of human HSPB8 and demonstrated that, like human HSPB8, Dm-HSP67Bc induces autophagy via the eIF2α pathway. In vitro, both Dm-HSP67Bc and human HSPB8 protected against mutated ataxin-3-mediated toxicity and decreased the aggregation of a mutated form of HSPB1 (P182L-HSPB1) associated with peripheral neuropathy. Up-regulation of both Dm-HSP67Bc and human HSPB8 protected and down-regulation of endogenous Dm-HSP67Bc significantly worsened SCA3-mediated eye degeneration in flies. The K141E and K141N mutated forms of human HSPB8 that are associated with peripheral neuropathy were significantly less efficient than wild-type HSPB8 in decreasing the aggregation of both mutated ataxin 3 and P182L-HSPB1. Our current data further support the link between the HSPB8-BAG3 complex, autophagy, and folding diseases and demonstrate that impairment or loss of function of HSPB8 might accelerate the progression and/or severity of folding diseases.
authors.affiliation: Department of Radiation and Stress Cell Biology, University Medical Center Groningen, A Deusinglaan 1, 9713 AV Groningen, The Netherlands.
authors.forename: Serena
authors.initials: S
authors.lastname: Carra
authors.forename: Alessandra
authors.initials: A
authors.lastname: Boncoraglio
authors.forename: Bart
authors.initials: B
authors.lastname: Kanon
authors.forename: Jeanette F
authors.initials: JF
authors.lastname: Brunsting
authors.forename: Melania
authors.initials: M
authors.lastname: Minoia
authors.forename: Anil
authors.initials: A
authors.lastname: Rana
authors.forename: Michel J
authors.initials: MJ
authors.lastname: Vos
authors.forename: Kay
authors.initials: K
authors.lastname: Seidel
authors.forename: Ody C M
authors.initials: OC
authors.lastname: Sibon
authors.forename: Harm H
authors.initials: HH
authors.lastname: Kampinga
mesh_terms: D000818:Animals; D001343:Autophagy; D004195:Disease Models, Animal; D004330:Drosophila / Q000235:genetics / Q000378:metabolism*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics / Q000378:metabolism; D005123:Eye / Q000378:metabolism; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D018832:Molecular Chaperones; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D057165:Proteostasis Deficiencies / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D029721:Drosophila Proteins; D015852:Eukaryotic Initiation Factor-2; C413214:HSPB8 protein, human; D006360:Heat-Shock Proteins; C554551:Hsp67Bc protein, Drosophila; D018832:Molecular Chaperones; D009419:Nerve Tissue Proteins; D017346:Protein Serine-Threonine Kinases