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Identification of the Drosophila ortholog of HSPB8: implication of HSPB8 loss of function in protein folding diseases.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2010 Nov 26; Vol. 285 (48), pp. 37811-22. Date of Electronic Publication: 2010 Sep 21. - Publication Year :
- 2010
-
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.
- Subjects :
- Animals
Autophagy
Disease Models, Animal
Drosophila genetics
Drosophila Proteins genetics
Eukaryotic Initiation Factor-2 genetics
Eukaryotic Initiation Factor-2 metabolism
Eye metabolism
Gene Expression Regulation
HEK293 Cells
Heat-Shock Proteins genetics
Humans
Molecular Chaperones
Nerve Tissue Proteins genetics
Nerve Tissue Proteins metabolism
Protein Serine-Threonine Kinases genetics
Proteostasis Deficiencies genetics
Proteostasis Deficiencies physiopathology
Drosophila metabolism
Drosophila Proteins metabolism
Heat-Shock Proteins metabolism
Protein Serine-Threonine Kinases metabolism
Proteostasis Deficiencies metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 285
- Issue :
- 48
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 20858900
- Full Text :
- https://doi.org/10.1074/jbc.M110.127498