title: Translocation of profilaggrin N-terminal domain into keratinocyte nuclei with fragmented DNA in normal human skin and loricrin keratoderma.
abstract: The terminal differentiation of epidermal keratinocytes from the granular to enucleated cornified layer involves drastic changes both in morphology and biochemistry. Profilaggrin is a keratinocyte-specific phosphoprotein expressed in the granular layer. Although keratinization has been regarded as a specialized form of apoptosis or programmed cell death, the mechanism for this cellular transition at the molecular level is not yet well understood. In this study, we used light and electron microscopic immunohistochemistry to investigate the localization of the profilaggrin domains during this process. Antibodies specific for the amino-terminal domains of profilaggrin showed localization in keratohyalin granules in the granular cells, but stained the nucleus in transition cells. In contrast, an antibody to filaggrin domains stained the cytoplasm in the transition cells. Nuclei that were positive to amino-terminal profilaggrin contained fragmented DNA, characteristic of apoptosis. In the epidermis of patients with progressive symmetric erythrokeratoderma carrying a mutation in the loricrin gene (loricrin keratoderma), the profilaggrin amino-terminal domains were packed within apoptotic nuclei together with loricrin aggregates and this persisted up to the parakeratotic superficial layer. The present study indicates that the amino-terminal profilaggrin domains are cleaved from the filaggrin repeats and transiently localized to the apoptotic nuclei just before the formation of enucleated stratum corneum in normal epidermis. This suggests a significant role for the profilaggrin amino-terminus in nuclear events associated with keratinocyte terminal differentiation. Disrupted apoptosis found in loricrin keratoderma might explain the marked parakeratotic hyperkeratosis characteristic of this disease.
authors.affiliation: Department of Dermatology, Asahikawa Medical College, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Ishida-Yamamoto
authors.forename: H
authors.initials: H
authors.lastname: Takahashi
authors.forename: R B
authors.initials: RB
authors.lastname: Presland
authors.forename: B A
authors.initials: BA
authors.lastname: Dale
authors.forename: H
authors.initials: H
authors.lastname: Iizuka
mesh_terms: D001706:Biopsy; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure*; D053938:DNA Fragmentation; D000091344:Filaggrin Proteins; D006801:Humans; D007150:Immunohistochemistry; D007381:Intermediate Filament Proteins / Q000378:metabolism*; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D007642:Keratosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010446:Peptide Fragments / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D011498:Protein Precursors / Q000378:metabolism*; D012016:Reference Values; D012867:Skin / Q000166:cytology* / Q000378:metabolism / Q000473:pathology*
chemical_list: C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins; D010446:Peptide Fragments; D010750:Phosphoproteins; D011498:Protein Precursors