Werner, Nicola Susann;
Windoffer, Reinhard;
Strnad, Pavel;
Grund, Christine;
Leube, Rudolf Eberhard;
Magin, Thomas Michael
Epidermolysis Bullosa Simplex-Type Mutations Alter the Dynamics of the Keratin Cytoskeleton and Reveal a Contribution of Actin to the Transport of Keratin Subunits
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Medientyp:
E-Artikel
Titel:
Epidermolysis Bullosa Simplex-Type Mutations Alter the Dynamics of the Keratin Cytoskeleton and Reveal a Contribution of Actin to the Transport of Keratin Subunits
Beteiligte:
Werner, Nicola Susann;
Windoffer, Reinhard;
Strnad, Pavel;
Grund, Christine;
Leube, Rudolf Eberhard;
Magin, Thomas Michael
Erschienen:
American Society for Cell Biology (ASCB), 2004
Erschienen in:Molecular Biology of the Cell
Sprache:
Englisch
DOI:
10.1091/mbc.e03-09-0687
ISSN:
1059-1524;
1939-4586
Entstehung:
Anmerkungen:
Beschreibung:
<jats:p>Dominant keratin mutations cause epidermolysis bullosa simplex by transforming keratin (K) filaments into aggregates. As a first step toward understanding the properties of mutant keratins in vivo, we stably transfected epithelial cells with an enhanced yellow fluorescent protein-tagged K14R<jats:sub>125</jats:sub>C mutant. K14R<jats:sub>125</jats:sub>C became localized as aggregates in the cell periphery and incorporated into perinuclear keratin filaments. Unexpectedly, keratin aggregates were in dynamic equilibrium with soluble subunits at a half-life time of <15 min, whereas filaments were extremely static. Therefore, this dominant-negative mutation acts by altering cytoskeletal dynamics and solubility. Unlike previously postulated, the dominance of mutations is limited and strictly depends on the ratio of mutant to wild-type protein. In support, K14R<jats:sub>125</jats:sub>C-specific RNA interference experiments resulted in a rapid disintegration of aggregates and restored normal filaments. Most importantly, live cell inhibitor studies revealed that the granules are transported from the cell periphery inwards in an actin-, but not microtubule-based manner. The peripheral granule zone may define a region in which keratin precursors are incorporated into existing filaments. Collectively, our data have uncovered the transient nature of keratin aggregates in cells and offer a rationale for the treatment of epidermolysis bullosa simplex by using short interfering RNAs.</jats:p>