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Institut
National de la Sante et de la Recherche Medicale (LG-P, YG, J-PO, GM), Faculte
de Medecine, and Service de Dermatologie (J-PO), Hopital de l'Archet 2,
Nice, France |
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The cytoplasmic domain of
integrin [beta]4, which contains four type III fibronectin-like motifs,
seems to be involved in the regulation of the assembly of hemidesmosomes
(HD) and, therefore, in cell adhesion. An in-frame deletion of 17 amino
acids in the second fibronectin type III repeat of integrin [beta]4 ([Delta]17-[beta]4)
has been associated with junctional epidermolysis bullosa with pyloric atresia
(PA-JEB), a genetic disease characterized by altered HD and disadhesion
of the epidermis. To determine the effect of deletion [Delta]17-[beta]4
on HD assembly, we have examined the expression and localization of the
HD components in the skin and cultured keratinocytes of a patient with PA-JEB,
which express the mutated integrin [beta]4. Our results show that the mutated
[beta]4 subunit associates with integrin [alpha]6, but the resulting heterodimer
does not induce nucleation of the bullous pemphigoid antigens BP180 and
BP230, and that of the inner plaque component plectin/HD1, into hemidesmosomal
structures. The integrity of the cytoplasmic tail of integrin [beta]4 seems
to be essential to the targeting and stabilization of plectin/HD1 and BP180
in HD, because transfection of a recombinant wild-type [beta]4 cDNA in the
[Delta]17-[beta]4 PA-JEB keratinocytes restores the synthesis of a functional
[alpha]6[beta]4 heterodimer, which promotes the polarization of plectin/HD1
and BP180, to the basal aspect of the cells. Because in the transfected
keratinocytes the distribution of BP230 remains diffuse in the cytoplasm,
we suggest that the interaction between plectin/HD1 and integrin [alpha]6[beta]4,
followed by the association with BP180, constitutes the first step in the
nucleation of the HD. |
