Invited review articlePlectin-related skin diseases
Introduction
Plectin is a versatile linker protein that is expressed ubiquitously in many tissues, including skin, muscle and tissues of the nervous system. Plectin was originally characterized as an intermediate filament (IF)-linker protein, but it also serves as a binding partner to actin, microtubules and other membranous proteins, including hemidesmosomes and focal contact proteins [1], [2]. In studies of plectin, the complexity mostly derives from the diversity of its isoforms. In humans, several splicing transcripts at the 5′ end of PLEC, which encodes plectin, lead to plectin 1 and 1a to 1 g isoforms in which the first coding exons are mutually distinct (Fig. 1) (Table 1) [3]. Each isoform tends to have a preference for cell-type-specific or organelle-specific expression: isoform 1 for nucleus/ER membrane [4], 1a for hemidesmosomes in epidermal keratinocytes [5], 1b for mitochondria [4], [6], 1c for microtubules [7], 1d for the Z-disk in skeletal muscle [8] and 1f for focal adhesion contacts [4]. It is noteworthy that the nomenclature of PLEC mutations is based on the numbering of the coding sequences of transcript variant 1 (NM_000445), which encodes plectin 1c [9], unless the mutations occur in the other isoform-specific first coding exons (e.g., exon 1a, exon 1f) [10], [11]. In addition to 5′ splicing diversity, exon 31 of PLEC, which encodes the rod domain of plectin, can be spliced out in the rodless transcripts (Fig. 2) [12]. The basic biology of plectin has been recently reviewed from Dr. Wiche's group [1], [2], and he and his collaborators have greatly contributed to this field. Accordingly, this review focuses on the pathological aspects of plectin in skin diseases, such as in congenital and autoimmune blistering diseases.
Section snippets
Epidermolysis bullosa
Epidermolysis bullosa (EB) is a heterogeneous group of disorders characterized by congenital skin fragility and blister formation. Mutations in the genes encoding basement-membrane-zone (BMZ) proteins or other junctional proteins are responsible for EB phenotypes. EB has three major types and one minor type, depending on the ultrastructural level of skin detachment: EB simplex (EBS; cell lysis of basal or spinous layers), junctional EB (JEB; skin separation at the lamina lucida), dystrophic EB
Autoimmune blistering diseases with autoantibodies to plectin
Autoimmune blistering diseases are a group of disorders in which circulating autoantibodies target BMZ or desmosomal proteins and cause skin fragility. In addition to the major autoantigens such as desmoglein 1/3 in pemphigus and COL17 in bullous pemphigoid (BP), plectin has been listed as a protein targeted by circulating autoantibodies. Circulating anti-plectin antibodies were first detected in paraneoplastic pemphigus (PNP) patients [47], [48]. In line with this, 23 out of 28 PNP patients
Concluding remarks
Tremendous advances regarding plectin-related skin diseases have been achieved in the past two decades; however, many unsolved problems remain, mostly those discussed above. Table 3 summarizes the unsolved questions in this field. Furthermore, the development of treatment modalities for plectin-related EBS is essential. This is particularly true for EBS-PA, which typically leads to early demise even when pyloric atresia is surgically corrected. Bone marrow transplantation has been tried for JEB
Funding source
None.
Acknowledgements
I thank Drs. Hiroshi Shimizu and Wataru Nishie (Hokkaido University Graduate School of Medicine, Sapporo, Japan) for their continuous encouragement and support and Ms. Meari Yoshida for assistance in preparing the tables.
Ken Natsuga (M.D., Ph.D.) is a dermatologist at the Hokkaido University Graduate School of Medicine in Sapporo, Japan. He received his M.D. degree from the Hokkaido University School of Medicine in 2003. He researched the pathomechanisms of epidermolysis bullosa and bullous pemphigoid and received his Ph.D. degree from the Hokkaido University Graduate School of Medicine in 2010. He worked as a postdoctoral researcher at Cancer Research UK in Cambridge, U.K., from 2010 to 2012 under the
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Wnt/β-Catenin Signaling Stabilizes Hemidesmosomes in Keratinocytes
2022, Journal of Investigative DermatologyCitation Excerpt :Because HD components were comparable in the soluble fraction but were reduced in the HD-rich fraction of the Wnt-inhibited cells (Figure 1a–d and Supplementary Figure S2), we hypothesized that Wnt inhibition leads to HD disassembly, causing the diffusion of HD components into the non-HD plasma membrane. We studied the functions of PCN to confirm this hypothesis further because this protein is a linker between intermediate filaments and HD components to assemble and maintain HDs (Castañón et al., 2013; Natsuga, 2015). We generated PCN-null HaCaT cells (PLEC knockout [KO]) using the CRISPR-Cas9 system.
Laryngeal lesion associated with epidermolysis bullosa secondary to congenital plectin deficiency
2019, Annales Francaises d'Oto-Rhino-Laryngologie et de Pathologie Cervico-FacialeLaryngeal lesion associated with epidermolysis bullosa secondary to congenital plectin deficiency
2019, European Annals of Otorhinolaryngology, Head and Neck DiseasesPhenotypic Spectrum of Epidermolysis Bullosa: The Paradigm of Syndromic versus Non-Syndromic Skin Fragility Disorders
2019, Journal of Investigative DermatologyCitation Excerpt :In particular, constitutive splicing out of exon 32 results in the synthesis of a rodless isoform of plectin, with amino- and carboxy-terminal globular domains linked together. Examination of distinct autosomal recessive cases of EBS-MD or EBS-PA has shown that loss of the full-length plectin isoform with some expression of the rodless plectin leads to EBS-MD, whereas complete loss or marked diminution in both full-length and rodless plectin expression results in EBS-PA (Natsuga, 2015). Based on these observations, it was concluded that PLEC mutations that are exclusively within exon 32 encoding the plectin rod domain result in EBS-MD, whereas PLEC mutations in EBS-PA are outside of exon 32.
SnapshotDx Quiz: July 2018
2018, Journal of Investigative DermatologyFibroblasts change spreading capability and mechanical properties in a direct interaction with keratinocytes in conditions mimicking wound healing
2018, Journal of BiomechanicsCitation Excerpt :Epidermis and dermis are separated by basal membrane, organization of which (in adult skin) results partially from the cooperative interaction between fibroblasts and keratinocytes through production of extracellular matrix proteins (El Ghalbzouri and Ponec, 2004; Sorrell and Caplan, 2004). Any alterations in basal membrane structure and integrity result in fragility, extensive blistering, wounds, congenital skin disorders or cancers, including malignant melanoma (Carr and Sanders, 2007; Natsuga, 2015; Segre, 2006). The interaction between fibroblasts and keratinocytes has been already studied in various skin aspects, such as differentiation of osteoclasts in cholesteatoma-induced bone destruction (Iwamoto et al., 2016), myofibroblasts differentiation in wound healing (Shephard et al., 2004; Werner et al., 2007), formation of basal membrane (Kehe et al., 1999; Smola et al., 1998) or upregulation of growth factors influencing the cellular proliferation (Sivamani et al., 2007; Gallucci et al., 2004).
Ken Natsuga (M.D., Ph.D.) is a dermatologist at the Hokkaido University Graduate School of Medicine in Sapporo, Japan. He received his M.D. degree from the Hokkaido University School of Medicine in 2003. He researched the pathomechanisms of epidermolysis bullosa and bullous pemphigoid and received his Ph.D. degree from the Hokkaido University Graduate School of Medicine in 2010. He worked as a postdoctoral researcher at Cancer Research UK in Cambridge, U.K., from 2010 to 2012 under the supervision of Prof. Fiona Watt. He received a postdoctoral fellowship for research abroad from the JSPS during his stay in the U.K. After returning to Japan, he was appointed as an assistant professor in the Department of Dermatology, Hokkaido University Graduate School of Medicine, chaired by Prof. Hiroshi Shimizu. His research interests include blistering diseases, keratinocyte differentiation and skin microbiota.