TRANSLOCATION OF PROFILAGGRIN N-TERMINAL DOMAIN INTO KERATINOCYTE NUCLEI WITH FRAGMENTED DNA IN NORMAL HUMAN SKIN AND LORICRIN KERATODERMA

The terminal differentiation of epidermal keratinocytes from the granu lar to enucleated cornified layer involves drastic changes both in mor phology and biochemistry. Profilaggrin is a keratinocyte-specific phos phoprotein expressed in the granular layer. Although keratinization ha s been regarded as a specialized form of apoptosis or programmed cell death, the mechanism for this cellular transition at the molecular lev el is not yet well understood. In this study, we used light and electr on 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 ker atohyalin granules in the granular cells, but stained the nucleus in t ransition cells. In contrast, an antibody to filaggrin domains stained the cytoplasm in the transition cells. Nuclei that were positive to a mino-terminal profilaggrin contained fragmented DNA, characteristic of apoptosis. In the epidermis of patients with progressive symmetric er ythrokeratoderma carrying a mutation in the loricrin gene (loricrin ke ratoderma), 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 indicate s that the amino-terminal profilaggrin domains are cleaved from the fi laggrin repeats and transiently localized to the apoptotic nuclei just before the formation of enucleated stratum corneum in normal epidermi s. This suggests a significant role for the profilaggrin amino-terminu s in nuclear events associated with keratinocyte terminal differentiat ion. Disrupted apoptosis found in loricrin keratoderma might explain t he marked parakeratotic hyperkeratosis characteristic of this disease.