title: Plectin-isoform-specific rescue of hemidesmosomal defects in plectin (-/-) keratinocytes.
abstract: The various plectin isoforms are among the major crosslinking elements of the cytoskeleton. The importance of plectin in epithelia is convincingly supported by the severe skin blistering observed in plectin-deficient humans and mice. Here, we identified plectin 1a (> 500 kDa), a full length plectin variant containing the sequence encoded by the alternative first exon 1a, as the isoform most prominently expressed in human and mouse keratinocytes. In skin sections and cultured keratinocytes, plectin 1a was shown to colocalize with hemidesmosomal structures. In contrast, a second isoform expressed in epithelia, plectin 1c, differing from 1a merely by a short N-terminal sequence, colocalized with microtubules. Expression of plectin 1a, but not of its N-terminal fragment alone, or of a third alternative full length isoform (plectin 1), restored the reduced number of hemidesmosome-like stable anchoring contacts in cultured plectin-null keratinocytes. Our results show for the first time that different isoforms of a cytolinker protein expressed in one cell type perform distinct functions. Moreover, the identification of plectin 1a as the isoform defects in which cause skin blistering in plectin-related genetic diseases, such as epidermolysis bullosa simplex MD and epidermolysis bullosa simplex Ogna, could have implications for the future development of clinical therapies for patients.
authors.affiliation: Institute of Biochemistry and Molecular Cell Biology, Vienna Biocenter, University of Vienna, Austria.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Andrä
authors.forename: Iris
authors.initials: I
authors.lastname: Kornacker
authors.forename: Almut
authors.initials: A
authors.lastname: Jörgl
authors.forename: Michael
authors.initials: M
authors.lastname: Zörer
authors.forename: Daniel
authors.initials: D
authors.lastname: Spazierer
authors.forename: Peter
authors.initials: P
authors.lastname: Fuchs
authors.forename: Irmgard
authors.initials: I
authors.lastname: Fischer
authors.forename: Gerhard
authors.initials: G
authors.lastname: Wiche
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D001768:Blister / Q000503:physiopathology; D002461:Cell Line, Transformed; D003599:Cytoskeleton / Q000737:chemistry; D003896:Desmosomes / Q000502:physiology*; D016110:Epidermolysis Bullosa Simplex / Q000503:physiopathology; D005091:Exons; D007381:Intermediate Filament Proteins / Q000032:analysis / Q000737:chemistry / Q000235:genetics*; D007536:Isomerism; D015603:Keratinocytes / Q000737:chemistry / Q000166:cytology / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D010446:Peptide Fragments / Q000235:genetics; D051190:Plectin; D014162:Transfection
chemical_list: D007381:Intermediate Filament Proteins; D010446:Peptide Fragments; C495333:Plec protein, mouse; D051190:Plectin