Identification of the Drosophila Ortholog of HSPB8: IMPLICATION OF HSPB8 LOSS OF FUNCTION IN PROTEIN FOLDING DISEASES* |
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Authors: | 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 |
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Institution: | From the ‡Department of Radiation and Stress Cell Biology, University Medical Center Groningen, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands and ;the §Department of Pathology and Medical Biology, University Medical Centre Groningen, Hanzeplein 1, 9713 RB Groningen, The Netherlands |
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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. |
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Keywords: | Autophagy Chaperone Chaperonin Drosophila Mutant Polyglutamine Disease Molecular Chaperones Mutated HSPB8 |
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