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PMID:19478074

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Citation

Kim, BY, Olzmann, JA, Choi, SI, Ahn, SY, Kim, TI, Cho, HS, Suh, H and Kim, EK (2009) Corneal dystrophy-associated R124H mutation disrupts TGFBI interaction with Periostin and causes mislocalization to the lysosome. J. Biol. Chem. 284:19580-91

Abstract

The 5q31-linked corneal dystrophies are heterogeneous autosomal-dominant eye disorders pathologically characterized by the progressive accumulation of aggregated proteinaceous deposits in the cornea, which manifests clinically as severe vision impairment. The 5q31-linked corneal dystrophies are commonly caused by mutations in the TGFBI (transforming growth factor-beta-induced) gene. However, despite the identification of the culprit gene, the cellular roles of TGFBI and the molecular mechanisms underlying the pathogenesis of corneal dystrophy remain poorly understood. Here we report the identification of periostin, a molecule that is highly related to TGFBI, as a specific TGFBI-binding partner. The association of TGFBI and periostin is mediated by the amino-terminal cysteine-rich EMI domains of TGFBI and periostin. Our results indicate that the endogenous TGFBI and periostin colocalize within the trans-Golgi network and associate prior to secretion. The corneal dystrophy-associated R124H mutation in TGFBI severely impairs interaction with periostin in vivo. In addition, the R124H mutation causes aberrant redistribution of the mutant TGFBI into lysosomes. We also find that the periostin-TGFBI interaction is disrupted in corneal fibroblasts cultured from granular corneal dystrophy type II patients and that periostin accumulates in TGFBI-positive corneal deposits in granular corneal dystrophy type II (also known as Avellino corneal dystrophy). Together, our findings suggest that TGFBI and periostin may play cooperative cellular roles and that periostin may be involved in the pathogenesis of 5q31-linked corneal dystrophies.

Links

PubMed PMC2740584 Online version:10.1074/jbc.M109.013607

Keywords

Adult; Amino Acid Substitution; Animals; Binding Sites/genetics; Blotting, Western; COS Cells; Cell Adhesion Molecules/genetics; Cell Adhesion Molecules/metabolism; Cell Line; Cells, Cultured; Cercopithecus aethiops; Cornea/cytology; Cornea/metabolism; Corneal Dystrophies, Hereditary/genetics; Corneal Dystrophies, Hereditary/pathology; Golgi Apparatus/metabolism; Green Fluorescent Proteins/genetics; Green Fluorescent Proteins/metabolism; HeLa Cells; Humans; Immunohistochemistry; Lysosomes/metabolism; Microscopy, Fluorescence; Middle Aged; Mutation; Protein Binding; Recombinant Fusion Proteins/genetics; Recombinant Fusion Proteins/metabolism; Transfection; Transforming Growth Factor beta1/genetics; Transforming Growth Factor beta1/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:CO6A5

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q15582

F

  • occurs_in:(CL:0002363)

Seeded From UniProt

complete

HUMAN:POSTN

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q15582

F

Seeded From UniProt

complete

HUMAN:POSTN

located_in

GO:0005802: trans-Golgi network

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:POSTN

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q15582

F

  • occurs_in:(CL:0002363)

Seeded From UniProt

complete

HUMAN:BGH3

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q15063

F

Seeded From UniProt

complete

HUMAN:BGH3

located_in

GO:0005615: extracellular space

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:BGH3

located_in

GO:0005802: trans-Golgi network

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:BGH3

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q15063

F

  • occurs_in:(CL:0002363)

Seeded From UniProt

complete

HUMAN:BGH3

enables

GO:0005518: collagen binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:A8TX70

F

Seeded From UniProt

complete

HUMAN:BGH3

part_of

GO:0005802: trans-Golgi network

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:BGH3

part_of

GO:0005615: extracellular space

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

Notes

See also

References

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