The mechanisms of hsp27 antibody-mediated apoptosis in retinal neuronal cells.
Although elevated titers of serum antibodies to hsp27 accompany human diseases such as cancer and glaucoma, evidence of their pathogenic effects is lacking. Here we present novel evidence that exogenously applied hsp27 antibody enters neuronal cells in human retina by an endocytic mechanism. Subsequent to internalization, hsp27 antibody facilitates apoptotic cell death as characterized by morphological assessment, DNA fragmentation, and the activation of cysteine aspartic acid proteases. In addition, we demonstrate that after internalization, hsp27 antibody is detected in discrete cytoplasmic and nuclear structures and colocalizes to actin cytoskeleton. Hsp27 antibody binding to actin results in depolymerization and proteolytic cleavage of actin in a dose-dependent manner. These results suggest that exogenous hsp27 antibody may induce neuronal apoptosis by inactivating or attenuating the ability of native hsp27 to stabilize actin cytoskeleton, thereby providing a novel mechanism by which autoantibodies to hsp27 may impair cell survival in selective human diseases.
Tezel
G
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Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Wax
M B
MB
D008841:Actin Cytoskeleton / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics*; D017209:Apoptosis / Q000276:immunology*; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002461:Cell Line, Transformed; D004705:Endocytosis / Q000276:immunology; D005434:Flow Cytometry; D006360:Heat-Shock Proteins / Q000276:immunology*; D006801:Humans; D020287:In Situ Nick-End Labeling; D008854:Microscopy, Electron; D008875:Middle Aged; D009475:Neurons, Afferent / Q000737:chemistry / Q000201:enzymology / Q000648:ultrastructure; D051381:Rats; D012160:Retina / Q000737:chemistry / Q000166:cytology* / Q000201:enzymology
D000199:Actins; D000911:Antibodies, Monoclonal; D006360:Heat-Shock Proteins; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; C505410:Casp3 protein, rat; C505528:Casp8 protein, rat; C506435:Casp9 protein, rat; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases