title: Analysis of the cytoprotective role of α-crystallins in cell survival and implication of the αA-crystallin C-terminal extension domain in preventing Bax-induced apoptosis.
abstract: α-Crystallins, initially described as the major structural proteins of the lens, belong to the small heat shock protein family. Apart from their function as chaperones, α-crystallins are involved in the regulation of intracellular apoptotic signals. αA- and αB-crystallins have been shown to interfere with the mitochondrial apoptotic pathway triggering Bax pro-apoptotic activity and downstream activation of effector caspases. Differential regulation of α-crystallins has been observed in several eye diseases such as age-related macular degeneration and stress-induced and inherited retinal degenerations. Although the function of α-crystallins in healthy and diseased retina remains poorly understood, their altered expression in pathological conditions argue in favor of a role in cellular defensive response. In the Rpe65⁻/⁻ mouse model of Leber's congenital amaurosis, we previously observed decreased expression of αA- and αB-crystallins during disease progression, which was correlated with Bax pro-death activity and photoreceptor apoptosis. In the present study, we demonstrated that α-crystallins interacted with pro-apoptotic Bax and displayed cytoprotective action against Bax-triggered apoptosis, as assessed by TUNEL and caspase assays. We further observed in staurosporine-treated photoreceptor-like 661W cells stably overexpressing αA- or αB-crystallin that Bax-dependent apoptosis and caspase activation were inhibited. Finally, we reported that the C-terminal extension domain of αA-crystallin was sufficient to provide protection against Bax-triggered apoptosis. Altogether, these data suggest that α-crystallins interfere with Bax-induced apoptosis in several cell types, including the cone-derived 661W cells. They further suggest that αA-crystallin-derived peptides might be sufficient to promote cytoprotective action in response to apoptotic cell death.
authors: IRO, Institute for Research in Ophthalmology, Sion, Switzerland.
authors: Séverine
authors: S
authors: Hamann
authors: Sylviane
authors: S
authors: Métrailler
authors: Daniel F
authors: DF
authors: Schorderet
authors: Sandra
authors: S
authors: Cottet
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000235:genetics / Q000502:physiology*; D003001:Cloning, Molecular; D019610:Cytoprotection / Q000235:genetics / Q000502:physiology*; D017931:DNA Primers / Q000235:genetics; D005822:Genetic Vectors; D057809:HEK293 Cells; D006801:Humans; D047468:Immunoprecipitation; D020287:In Situ Nick-End Labeling; D016086:Lentivirus; D051379:Mice; D008856:Microscopy, Fluorescence; D038202:alpha-Crystallin A Chain / Q000235:genetics / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
chemical_list: C494827:Bax protein, mouse; D017931:DNA Primers; D038202:alpha-Crystallin A Chain; D051028:bcl-2-Associated X Protein; D020169:Caspases
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