Filensin (Beaded filament structural protein 1) (Lens fiber cell beaded-filament structural protein CP 115) (CP115) (Lens intermediate filament-like heavy) (LIFL-H) [Contains: Filensin C-terminal fragment; Filensin N-terminal fragment]

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The oxidized thiol proteome in aging and cataractous mouse and human lens revealed by ICAT labeling.

Age-related cataractogenesis is associated with disulfide-linked high molecular weight (HMW) crystallin aggregates. We recently found that the lens crystallin disulfidome was evolutionarily conserved in human and glutathione-depleted mouse (LEGSKO) cataracts and that it could be mimicked by oxidation in vitro (Mol. Cell Proteomics, 14, 3211-23 (2015)). To obtain a comprehensive blueprint of the oxidized key regulatory and cytoskeletal proteins underlying cataractogenesis, we have now used the same approach to determine, in the same specimens, all the disulfide-forming noncrystallin proteins identified by ICAT proteomics. Seventy-four, 50, and 54 disulfide-forming proteins were identified in the human and mouse cataracts and the in vitro oxidation model, respectively, of which 17 were common to all three groups. Enzymes with oxidized cysteine at critical sites include GAPDH (hGAPDH, Cys247), glutathione synthase (hGSS, Cys294), aldehyde dehydrogenase (hALDH1A1, Cys126 and Cys186), sorbitol dehydrogenase (hSORD, Cys140, Cys165, and Cys179), and PARK7 (hPARK7, Cys46 and Cys53). Extensive oxidation was also present in lens-specific intermediate filament proteins, such as BFSP1 and BFSP12 (hBFSP1 and hBFSP12, Cys167, Cys65, and Cys326), vimentin (mVim, Cys328), and cytokeratins, as well as microfilament and microtubule filament proteins, such as tubulin and actins. While the biological impact of these modifications for lens physiology remains to be determined, many of these oxidation sites have already been associated with either impaired metabolism or cytoskeletal architecture, strongly suggesting that they have a pathogenic role in cataractogenesis. By extrapolation, these findings may be of broader significance for age- and disease-related dysfunctions associated with oxidant stress.

MeSH Terms

  • Adolescent
  • Aged
  • Aging
  • Amino Acid Sequence
  • Animals
  • Antioxidants
  • Cataract
  • Child
  • Child, Preschool
  • Cross-Linking Reagents
  • Cysteine
  • Glutathione
  • Humans
  • Intermediate Filaments
  • Isotope Labeling
  • Lens, Crystalline
  • Mice, Knockout
  • Oxidation-Reduction
  • Peptides
  • Protein Deglycase DJ-1
  • Proteome
  • Sulfhydryl Compounds

Keywords

  • aging
  • cataractogenesis
  • disulfide
  • mass spectrometry
  • proteomics
  • reactive oxygen species


Functions of the intermediate filament cytoskeleton in the eye lens.

Intermediate filaments (IFs) are a key component of the cytoskeleton in virtually all vertebrate cells, including those of the lens of the eye. IFs help integrate individual cells into their respective tissues. This Review focuses on the lens-specific IF proteins beaded filament structural proteins 1 and 2 (BFSP1 and BFSP2) and their role in lens physiology and disease. Evidence generated in studies in both mice and humans suggests a critical role for these proteins and their filamentous polymers in establishing the optical properties of the eye lens and in maintaining its transparency. For instance, mutations in both BFSP1 and BFSP2 cause cataract in humans. We also explore the potential role of BFSP1 and BFSP2 in aging processes in the lens.

MeSH Terms

  • Aging
  • Animals
  • Cataract
  • Eye Proteins
  • Humans
  • Intermediate Filament Proteins
  • Intermediate Filaments
  • Lens, Crystalline
  • Mice
  • Mutation
  • Vimentin
  • alpha-Crystallin B Chain