Modelling cortical cataractogenesis XXIX. Calpain proteolysis of lens fodrin in cataract

Kilic, Fusun; Trevithick, John R.

doi:10.1002/iub.7510450514

Cited by 27 publications

(36 citation statements)

References 22 publications

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“…Calpain is one of the dominant proteases in mammalian lenses. Fodrin, Filensin, and Vimentin are known substrates of calpain in lens (22)(23)(24), and the appearance of cleavage products suggests that there is elevated calpain activity in lenses in which K6W-Ub is expressed. Relationships between calpain and expression of K6W-Ub were examined using four different assays.…”

Section: Resultsmentioning

confidence: 99%

Altered ubiquitin causes perturbed calcium homeostasis, hyperactivation of calpain, dysregulated differentiation, and cataract

Liu

Lyu

Chin

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Although the ocular lens shares many features with other tissues, it is unique in that it retains its cells throughout life, making it ideal for studies of differentiation/development. Precipitation of proteins results in lens opacification, or cataract, the major blinding disease. Lysines on ubiquitin (Ub) determine fates of Ub-protein substrates. Information regarding ubiquitin proteasome systems (UPSs), specifically of K6 in ubiquitin, is undeveloped. We expressed in the lens a mutant Ub containing a K6W substitution (K6W-Ub). Protein profiles of lenses that express wild-type ubiquitin (WT-Ub) or K6W-Ub differ by only ∼2%. Despite these quantitatively minor differences, in K6W-Ub lenses and multiple model systems we observed a fourfold Ca2+ elevation and hyperactivation of calpain in the core of the lens, as well as calpain-associated fragmentation of critical lens proteins including Filensin, Fodrin, Vimentin, β-Crystallin, Caprin family member 2, and tudor domain containing 7. Truncations can be cataractogenic. Additionally, we observed accumulation of gap junction Connexin43, and diminished Connexin46 levels in vivo and in vitro. These findings suggest that mutation of Ub K6 alters UPS function, perturbs gap junction function, resulting in Ca2+ elevation, hyperactivation of calpain, and associated cleavage of substrates, culminating in developmental defects and a cataractous lens. The data show previously unidentified connections between UPS and calpain-based degradative systems and advance our understanding of roles for Ub K6 in eye development. They also inform about new approaches to delay cataract and other protein precipitation diseases.

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Section: Resultsmentioning

confidence: 99%

Altered ubiquitin causes perturbed calcium homeostasis, hyperactivation of calpain, dysregulated differentiation, and cataract

Liu

Lyu

Chin

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Interestingly, cleavage of ␣-spectrin by calpain, not by caspase, has been associated with a number of cataract models (41,53). Inhibition of calpain inhibits cataract formation and spectrin cleavage (54), and human lenses with age-related nuclear cataracts display a higher density of finger-like membrane projections than transparent lenses of the same age (55).…”

Section: Discussionmentioning

confidence: 99%

Caspase Remodeling of the Spectrin Membrane Skeleton during Lens Development and Aging

Lee

Morrow

Fowler

2001

Journal of Biological Chemistry

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Terminal differentiation of lens fiber cells resembles the apoptotic process in that organelles are lost, DNA is fragmented, and changes in membrane morphology occur. However, unlike classically apoptotic cells, which are disintegrated by membrane blebbing and vesiculation, aging lens fiber cells are compressed into the center of the lens, where they undergo cell-cell fusion and the formation of specialized membrane interdigitations. In classically apoptotic cells, caspase cleavage of the cytoskeletal protein ␣-spectrin to ϳ150-kDa fragments is believed to be important for membrane blebbing. We report that caspase(s) cleave ␣-spectrin to ϳ150-kDa fragments and ␤-spectrin to ϳ120-and ϳ80-kDa fragments during late embryonic chick lens development. These fragments continue to accumulate with age so that in the oldest fiber cells of the adult lens, most, if not all, of the spectrin is cleaved to discrete fragments. Thus, unlike classical apoptosis, where caspase-cleaved spectrin is short lived, lens fiber cells contain spectrin fragments that appear to be stable for the lifetime of the organism. Moreover, fragmentation of spectrin results in reduced membrane association and thus may lead to permanent remodeling of the membrane skeleton. Partial and specific proteolysis of membrane skeleton components by caspases may be important for age-related membrane changes in the lens.The spectrin-actin membrane skeleton underlies the plasma membranes of all cells and is important for cellular shape, membrane stability and deformability, as well as the formation of membrane subdomains (1). The major component of the membrane skeleton, spectrin, is composed of an ␣/␤ heterodimer that self-associates head-to-head to form a 200-nm extended tetramer filament. Spectrin cross-links actin filaments into an isotropic meshwork. This spectrin-actin meshwork is attached to the membrane by direct interactions of ␤-spectrin with membrane proteins and indirect interactions of ␤-spectrin with membrane attachment proteins such as ankyrin (2).Proteolysis of ␣-spectrin (␣II-spectrin, non-erythroid spectrin, or fodrin) to discrete fragments is implicated in changes in cell shape and membrane morphology which occur in many cell types. During platelet activation, which includes a cell shape transformation from discs into irregular spheres, spectrin is cleaved to ϳ150-kDa fragments by the calcium-dependent protease, calpain (3). ␣-Spectrin cleavage by calpain has also been implicated in cellular hypoxia (4), neuronal injury and degeneration (5), and neuronal growth cone formation (6). However, in apoptotic cells, ␣-spectrin proteolysis to ϳ150-kDa fragments is mediated by caspases; in these cells, spectrin proteolysis is thought to be important for the disintegration of the plasma membranes via formation of vesicular "apoptotic bodies" (7-12). Although calpain cleavage of spectrin is known to affect its ability to bind membranes or actin filaments (13, 14), the detailed consequences of caspase cleavage of spectrin have not been studied.The terminal ...

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“…Strong support for the role of calpain in precipitation of crystallins in selenite cataract has been provided by an in vitro model of proteolytic precipitation [32]. Recently, calcium elevation and parallel calpain proteolysis of fodrin, the cytoskeletal protein in the lens, has been shown to contribute to the development of cortical opacity [33]. However, what triggers this cascade of reactions in the lens, which finally culminates in opacification, is not yet very elusive, but involvement of free radicals is indicated.…”

Section: Discussionmentioning

confidence: 99%

Green Tea <i>(Camellia sinensis)</i> Protects against Selenite-Induced Oxidative Stress in Experimental Cataractogenesis

et al. 2002

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Cataract is the leading cause of blindness worldwide. It is a multifactorial disease primarily associated with oxidative stress produced by free radicals. The protection offered by various antioxidants in cataract development is well established. Polyphenolic compounds present in green tea (Camellia sinensis) are reported to possess antioxidant property in various pathological conditions. The present study was undertaken to evaluate the anticataract potential of green tea leaf (GTL) extract in the development of lens opacification. Enucleated rat lenses were randomly divided into normal, control and treated groups and incubated for 24 h at 37°C. Oxidative stress was induced by sodium selenite in the culture medium of the two groups (except the normal group). The medium of the treated group was additionally supplemented with GTL extract. After incubation, lenses were subjected to glutathione and malondialdehyde estimation. Enzyme activity of superoxide dismutase, catalase and glutathione peroxidase was also measured in different sets of the experiment. In vivo cataract was induced in 9-day-old rat pups of both control and treated groups by a single subcutaneous injection of sodium selenite. The treated pups were injected GTL extract intraperitoneally prior to selenite challenge and continued for 2 consecutive days thereafter. Cataract incidence was evaluated on 16th postnatal day by slit lamp examination. There was positive modulation of biochemical parameters in the organ culture study. Green tea was also found to reduce the incidence of selenite cataract in vivo. The results suggest that green tea possesses significant anticataract potential and acts primarily by preserving the antioxidant defense system.

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Modelling cortical cataractogenesis XXIX. Calpain proteolysis of lens fodrin in cataract

Cited by 27 publications

References 22 publications

Altered ubiquitin causes perturbed calcium homeostasis, hyperactivation of calpain, dysregulated differentiation, and cataract

Altered ubiquitin causes perturbed calcium homeostasis, hyperactivation of calpain, dysregulated differentiation, and cataract

Caspase Remodeling of the Spectrin Membrane Skeleton during Lens Development and Aging

Green Tea <i>(Camellia sinensis)</i> Protects against Selenite-Induced Oxidative Stress in Experimental Cataractogenesis

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