Mutant Loricrin is Not Crosslinked into the Cornified Cell Envelope but is Translocated into the Nucleus in Loricrin Keratoderma Akemi Ishida-Yamamoto,

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Mutant Loricrin is Not Crosslinked into the Cornified Cell Envelope but is Translocated into the Nucleus in Loricrin Keratoderma Akemi Ishida-Yamamoto, Satoshi Nakamura, Motoshi Kinouchi, Hidetoshi Takahashi, Hajime Iizuka Journal of Investigative Dermatology Volume 115, Issue 6, Pages 1088-1094 (December 2000) DOI: 10.1046/j.1523-1747.2000.00163.x Copyright © 2000 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Immunoblot detects mutant loricrin. Positive bands are detected in LK horny cells (lanes 2 and 3), but not in normal control (lane 1). Extracts from scraped horny cells were fractionated on 12.5% sodium dodecyl sulfate polyacrylamide gels and immunoblotted with the mlo2 antibody preincubated with 5 mM mutant loricrin peptide in TBS (lane 3) or with TBS (lanes 1 and 2) for 1 h at 37°C. The sizes of molecular weight standards are shown on the left. The square denotes the approximately 39 kDa mutant loricrin protein and circles are for its possible polymers. Journal of Investigative Dermatology 2000 115, 1088-1094DOI: (10.1046/j.1523-1747.2000.00163.x) Copyright © 2000 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Mutant loricrin is expressed within the nuclei of LK keratinocytes. Mutant (a-f) and wild-type loricrin (g) staining. Lesional skin (a-c, g), scraped sole skin horny layer (d), and nonlesional skin (e) from LK patients, and normal control skin (f). (a) Green fluorescence for mutant loricrin is detected within the differentiated keratinocyte nuclei. (b) Mutant loricrin is associated with globular intranuclear structures in the lower granular cells (arrowheads). (c) Preincubation of the antibody with mutant loricrin peptide abolishes immunoreaction. (d) Punctate staining in the scraped horny layer of LK sole skin. (e) The most superficial granular cells in the nonlesional skin also express mutant loricrin. (f) No reaction is detected in normal skin. (g) Normal loricrin is expressed in the cytoplasm as well as in the nucleus. Scale bars: 10 μm. Journal of Investigative Dermatology 2000 115, 1088-1094DOI: (10.1046/j.1523-1747.2000.00163.x) Copyright © 2000 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Mutant loricrin is accumulated on nucleolus. Cryostat sections of an LK patient were double stained for mutant loricrin antibody (green) and a nucleolar antigen (red). Nuclei are also stained with DAPI (blue). Merged figures of mutant loricrin and DAPI (a), a nucleolar antigen and DAPI (b), and all three staining (c). Arrows indicate mutant loricrin-positive nucleoli. Scale bar: 10 μm. Journal of Investigative Dermatology 2000 115, 1088-1094DOI: (10.1046/j.1523-1747.2000.00163.x) Copyright © 2000 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 Electron-dense nuclear granules appear around an inactive nucleolus in the differentiated LK keratinocytes. Transmission electron microscopy of normal (a, c) and LK (b, d) epidermis. (a, b) Active large reticulate nucleoli in the lower granular cells contain several fibrillar centers (c) surrounded by dense fibrillar component (d) and granular component (g). (c, d) Nuclei in upper granular cells have a nonactive small nucleolus. Electron-dense nuclear granules are unique to LK skin (d, arrowheads). Each nucleolus is shown in a lower magnification as an inset. ch, chromatin. Scale bar: 0.5 μm; 5 μm in insets. Journal of Investigative Dermatology 2000 115, 1088-1094DOI: (10.1046/j.1523-1747.2000.00163.x) Copyright © 2000 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 5 Mutant loricrin is associated with an active nucleolus. Immunoelectron microscopy of mutant (a, b) and wild-type (c) loricrin in LK epidermis. Nucleoli (arrows) in lower granular cells (a, c) and an upper granular cell (b). (a) Mutant loricrin is associated with dense fibrillar component (d) and granular component (g) of an active nucleolus. Fibrillar centers (c) are not labeled. (b) Mutant loricrin is on the periphery of an inactive nucleolus and in the nucleoplasm (arrowheads). (c) Wild-type loricrin is distributed diffusely, not particularly associating with nucleoli. Scale bar: 0.1 μm. Journal of Investigative Dermatology 2000 115, 1088-1094DOI: (10.1046/j.1523-1747.2000.00163.x) Copyright © 2000 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 6 Mutant loricrin is not crosslinked into CE, whereas wild-type loricrin is crosslinked but epitopes are masked. Immunoelectron microscopy for involucrin (5 nm gold) and mutant loricrin (10 nm gold) (a) and wild-type loricrin (b, c). Undigested (a, b) and proteinase-K-digested (5 min) (c) LK skin. (a) Along CE, there are many involucrin labels (arrowheads), but few labels for mutant loricrin (arrow). (b) Wild-type loricrin labeling is seen along the cell membrane (arrowheads) of the superficial granular cells (G), but not along the CE of the horny layer (H). ICS, intercellular space. (c) Proteinase K digestion has retrieved masked loricrin epitopes on the CE. Scale bars: 0.1 μm. Journal of Investigative Dermatology 2000 115, 1088-1094DOI: (10.1046/j.1523-1747.2000.00163.x) Copyright © 2000 The Society for Investigative Dermatology, Inc Terms and Conditions