MentsWe thank Dr. A. Takada for kindly providing mice adapted PR/8 virus. We also thank Dr. JC Reed for discussion and comments.Author ContributionsConceived and designed the get GGTI298 experiments: DF TM. Performed the experiments: DF SC DM MK YN. Analyzed the data: DF. Contributed reagents/materials/analysis tools: TK SA HK. Wrote the paper: DF TM.
a-Crystallins, the major structural proteins of the mammalian lens, encompass aA- and aB-crystallins, which are encoded by separate genes [1]. The two a-crystallins have molecular masses around 20 kDa each and share 55 amino acid identity. Their molecular structure is similar, containing three distinct domains: a highly conserved central a-crystallin domain of around 90 amino acids, flanked by a variable hydrophobic N-terminal domain and a hydrophilic C-terminal extension containing a conserved sequence motif [2?]. a-Crystallins belong to the small heat shock protein family of molecular ATP-independent chaperones. In mature lens fiber cells, they binds improperly folded proteins thereby preventing subsequent formation of light scattering aggregates [5]. Interactions between a-crystallins and putative substrates involve exposure of hydrophobic surfaces. However, emerging data support the idea that many sites may contribute to substrate interactions and that binding may be different according to the nature of the substrates [4,6]. Besides their chaperone-like activity [1,7], a-crystallins play a critical role in modulating various cellular processes such as oxidative stress, neuroprotection and GGTI298 site apoptosis pathways, eitherpromoting survival or inhibiting cell death [8]. In human lensderived epithelial cell line, a-crystallins interfere with UVAinduced apoptosis through different mechanisms, including PKCa, Raf/MEK/ERK and Akt signaling pathways. While aBcrystallin is able to abrogate apoptosis through repression of Raf/ MEK/ERK signal, aA-crystallin activates the Akt surviving pathway to inhibit triggered apoptosis [9]. In addition, aAcrystallin has been shown to inhibit apoptosis by enhancing phosphoinositide 3 kinase (PI3K) activity, which was related to its chaperone activity [10]. It has been observed that a-crystallins counteract the mitochondrial apoptotic pathway triggering the translocation of Bax at the mitochondria, the release of mitochondrial cytochrome C in the cytosol and the subsequent activation of downstream caspases including Caspase-3 [11]. In lens epithelial cells, interaction of a-crystallins with pro-apoptotic Bcl-2-related proteins and Caspase-3 prevents Bax and Bcl-XS mitochondrial translocation and caspase activation 1662274 [12,13]. They display cytoprotective action against staurosporine (STS)- and UVA-induced apoptosis [14,15,9]. a-Crystallins protect cells from metabolic stress [16] as well as apoptosis induced by various stress factors such as STS [15,17], TNF [15,18], calcium [19], anda-Crystallin Cytoprotective Actionhydrogen peroxide [20,21]. aB-crystallin can inhibit apoptosis induced by TRAIL [22], DNA-damaging agent and growth factor deprivation [23,24]. Microarray and proteome expression studies highlighted that aA- and aB-crystallins are expressed in normal and pathological retina [25?7]. Both proteins are detected in the ganglion cell layer as well as in the outer and inner nuclear layers of the retina [25]. During the course of retinal degeneration, a-crystallin expression is impaired in inherited retinal diseases in RCS rat [28,29] and rd mouse [27,30], after ischemia-repe.MentsWe thank Dr. A. Takada for kindly providing mice adapted PR/8 virus. We also thank Dr. JC Reed for discussion and comments.Author ContributionsConceived and designed the experiments: DF TM. Performed the experiments: DF SC DM MK YN. Analyzed the data: DF. Contributed reagents/materials/analysis tools: TK SA HK. Wrote the paper: DF TM.
a-Crystallins, the major structural proteins of the mammalian lens, encompass aA- and aB-crystallins, which are encoded by separate genes [1]. The two a-crystallins have molecular masses around 20 kDa each and share 55 amino acid identity. Their molecular structure is similar, containing three distinct domains: a highly conserved central a-crystallin domain of around 90 amino acids, flanked by a variable hydrophobic N-terminal domain and a hydrophilic C-terminal extension containing a conserved sequence motif [2?]. a-Crystallins belong to the small heat shock protein family of molecular ATP-independent chaperones. In mature lens fiber cells, they binds improperly folded proteins thereby preventing subsequent formation of light scattering aggregates [5]. Interactions between a-crystallins and putative substrates involve exposure of hydrophobic surfaces. However, emerging data support the idea that many sites may contribute to substrate interactions and that binding may be different according to the nature of the substrates [4,6]. Besides their chaperone-like activity [1,7], a-crystallins play a critical role in modulating various cellular processes such as oxidative stress, neuroprotection and apoptosis pathways, eitherpromoting survival or inhibiting cell death [8]. In human lensderived epithelial cell line, a-crystallins interfere with UVAinduced apoptosis through different mechanisms, including PKCa, Raf/MEK/ERK and Akt signaling pathways. While aBcrystallin is able to abrogate apoptosis through repression of Raf/ MEK/ERK signal, aA-crystallin activates the Akt surviving pathway to inhibit triggered apoptosis [9]. In addition, aAcrystallin has been shown to inhibit apoptosis by enhancing phosphoinositide 3 kinase (PI3K) activity, which was related to its chaperone activity [10]. It has been observed that a-crystallins counteract the mitochondrial apoptotic pathway triggering the translocation of Bax at the mitochondria, the release of mitochondrial cytochrome C in the cytosol and the subsequent activation of downstream caspases including Caspase-3 [11]. In lens epithelial cells, interaction of a-crystallins with pro-apoptotic Bcl-2-related proteins and Caspase-3 prevents Bax and Bcl-XS mitochondrial translocation and caspase activation 1662274 [12,13]. They display cytoprotective action against staurosporine (STS)- and UVA-induced apoptosis [14,15,9]. a-Crystallins protect cells from metabolic stress [16] as well as apoptosis induced by various stress factors such as STS [15,17], TNF [15,18], calcium [19], anda-Crystallin Cytoprotective Actionhydrogen peroxide [20,21]. aB-crystallin can inhibit apoptosis induced by TRAIL [22], DNA-damaging agent and growth factor deprivation [23,24]. Microarray and proteome expression studies highlighted that aA- and aB-crystallins are expressed in normal and pathological retina [25?7]. Both proteins are detected in the ganglion cell layer as well as in the outer and inner nuclear layers of the retina [25]. During the course of retinal degeneration, a-crystallin expression is impaired in inherited retinal diseases in RCS rat [28,29] and rd mouse [27,30], after ischemia-repe.
