Biosynthetic pathways of filaggrin and loricrin--two major proteins expressed by terminally differentiated epidermal keratinocytes.
We have used immunoelectron microscopy to map the biosynthetic pathways of loricrin and filaggrin in epidermal keratinocytes at successive stages of differentiation in newborn mouse skin. The filaggrin epitope is first detected in large, irregularly shaped, keratohyalin granules (F-granules) in the stratum granulosum, and then distributed throughout the cytoplasms of the innermost layers of stratum corneum cells. We conclude that the poly-protein filaggrin precursor is first accumulated in F-granules, from which it is subsequently released and processed into filaggrin, and becomes associated with the densely packed bundles of keratin filaments inside stratum corneum cells. Its diminished visibility in the outer layers correlates with the known degradation of filaggrin to free amino acids. Loricrin is first detected in small round keratohyalin granules (L-granules), and subsequently at the periphery of cells throughout the stratum corneum. Labeling of purified keratinocyte envelopes establishes that this loricrin epitope is exposed only at their inner (cytoplasmic) surface. Thus loricrin is initially accumulated in L-granules, to be released at a specifically programmed stage of keratinocyte maturation, and incorporated into the covalently cross-linked lining of the cell envelope. Since loricrin is rich in cysteine, L-granules account for the sulfur-rich keratohyalin granules described earlier. Proposals are made to rationalize why, subsequent to synthesis, filaggrin precursor and loricrin should be segregated both from each other and from the rest of the cytoplasm.
Steven
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AC
Laboratory of Structural Biology Research, National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland 20892.
Bisher
M E
ME
Roop
D R
DR
Steinert
P M
PM
D000595:Amino Acid Sequence; D000818:Animals; D000831:Animals, Newborn; D000911:Antibodies, Monoclonal; D002454:Cell Differentiation; D002478:Cells, Cultured; D003594:Cytoplasmic Granules / Q000648:ultrastructure; D000078404:Epidermal Cells; D004817:Epidermis / Q000378:metabolism / Q000648:ultrastructure; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins / Q000032:analysis / Q000096:biosynthesis*; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism* / Q000648:ultrastructure; D008565:Membrane Proteins / Q000032:analysis / Q000096:biosynthesis*; D051379:Mice; D016253:Microscopy, Immunoelectron; D008969:Molecular Sequence Data
D000911:Antibodies, Monoclonal; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins; D008565:Membrane Proteins; C064554:loricrin