Identification of the Drosophila Ortholog of HSPB8 IMPLICATION OF HSPB8 LOSS OF FUNCTION IN PROTEIN FOLDING DISEASES

Serena Carra*, Alessandra Boncoraglio, Bart Kanon, Jeanette F. Brunsting, Melania Minoia, Anil Rana, Michel J. Vos, Kay Seidel, Ody C. M. Sibon, Harm H. Kampinga

*Bijbehorende auteur voor dit werk

    OnderzoeksoutputAcademicpeer review

    56 Citaten (Scopus)

    Samenvatting

    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 eIF2 alpha-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 eIF2 alpha 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. Upregulation 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.

    Originele taal-2English
    Pagina's (van-tot)37811-37822
    Aantal pagina's12
    TijdschriftThe Journal of Biological Chemistry
    Volume285
    Nummer van het tijdschrift48
    DOI's
    StatusPublished - 26-nov-2010

    Citeer dit