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1.
Exp Dermatol ; 26(12): 1154-1162, 2017 12.
Article in English | MEDLINE | ID: mdl-28887824

ABSTRACT

The dermal-epidermal junction consists of a network of several interacting structural proteins that strengthen adhesion and mediate signalling events. This structural network consists of hemidesmosomal-anchoring filament complexes connecting the basal keratinocytes to the basement membrane. The anchoring filaments in turn interact with the anchoring fibrils to attach the basement membrane to the underlying dermis. Several of these structural proteins are recognized by autoantibodies in pemphigoid diseases, a heterogeneous group of clinically and immunopathologically diverse entities. Targeted proteins include the two intracellular plakins, plectin isoform 1a and BP230 (also called bullous pemphigoid antigen (BPAG) 1 isoform e (BPAG1e)). Plectin 1a and BP230 are connected to the intermediate filaments and to the cell surface receptor α6ß4 integrin, which in turn is connected to laminin 332, a component of the anchoring filaments. Further essential adhesion proteins are BP180, a transmembrane protein, laminin γ1 and type VII collagen. Latter protein is the major constituent of the anchoring fibrils. Mutations in the corresponding genes of these adhesion molecules lead to inherited epidermolysis bullosa emphasizing the importance of these proteins for the integrity of the dermal-epidermal junction. This review will provide an overview on the structure and function of the proteins situated in the dermal-epidermal junction targeted by autoantibodies.


Subject(s)
Autoantibodies/immunology , Skin Diseases, Vesiculobullous/immunology , Animals , Autoantigens/immunology , Collagen Type VII/immunology , Dystonin/immunology , Humans , Integrin alpha6beta4/immunology , Laminin/immunology , Non-Fibrillar Collagens/immunology , Plectin/immunology , Collagen Type XVII
2.
J Med Virol ; 87(6): 1060-5, 2015 Jun.
Article in English | MEDLINE | ID: mdl-25776836

ABSTRACT

Oral lichen planus is an idiopathic inflammatory disease of oral mucous membranes, characterized by an autoimmune epidermis attack by T cells. It remains unknown, however, how such aggressive T cells are activated in vivo to cause epidermal damage. This study analyzes the relationship at the peptide level between viruses and oral lichen planus disease. Four potentially immunogenic peptides (SSSSSSS, QEQLEKA, LLLLLLA, and MLSGNAG) are found to be shared between HCV, EBV, HHV-7, HSV-1, and CMV and three human proteins (namely pinin, desmoglein-3, and plectin). The described peptide sharing might be of help in deciphering the still unexplained immunopathogenic pathway that leads to oral lichen planus.


Subject(s)
Hepacivirus/chemistry , Herpesviridae/chemistry , Lichen Planus, Oral/etiology , Peptides/immunology , Viral Proteins/immunology , Cell Adhesion Molecules/chemistry , Cell Adhesion Molecules/immunology , Cytomegalovirus/chemistry , Desmoglein 3/chemistry , Desmoglein 3/immunology , Herpesvirus 1, Human/chemistry , Herpesvirus 4, Human/chemistry , Herpesvirus 7, Human/chemistry , Humans , Lichen Planus, Oral/immunology , Nuclear Proteins/chemistry , Nuclear Proteins/immunology , Peptide Library , Peptides/chemistry , Plectin/chemistry , Plectin/immunology , T-Lymphocytes/immunology , Viral Proteins/chemistry
3.
J Dermatol Sci ; 77(3): 139-45, 2015 Mar.
Article in English | MEDLINE | ID: mdl-25530118

ABSTRACT

Plectin has been characterized as a linker protein that is expressed in many cell types and is distinctive in various isoforms in the N-terminus and around the rod domain due to complicated alternative splicing of PLEC, the gene encoding plectin. Plectin deficiency causes autosomal recessive epidermolysis bullosa simplex (EBS) with involvement of the skin and other organs, such as muscle and gastrointestinal tract, depending on the expression pattern of the defective protein. In addition, a point mutation in the rod domain of plectin leads to autosomal dominant EBS, called as EBS-Ogna. Plectin can be targeted by circulating autoantibodies in subepidermal autoimmune blistering diseases. This review summarizes plectin-related skin diseases, from congenital to autoimmune disorders.


Subject(s)
Autoimmune Diseases/genetics , Epidermolysis Bullosa Simplex/genetics , Plectin/genetics , Plectin/immunology , Autoantibodies/blood , Autoimmune Diseases/immunology , Epidermolysis Bullosa Simplex/complications , Gastric Outlet Obstruction/complications , Gastric Outlet Obstruction/genetics , Humans , Muscular Dystrophies/complications , Muscular Dystrophies/genetics , Plectin/deficiency , Point Mutation , Pylorus/abnormalities , Skin Diseases, Vesiculobullous/genetics , Skin Diseases, Vesiculobullous/immunology
4.
Br J Dermatol ; 161(4): 762-71, 2009 Oct.
Article in English | MEDLINE | ID: mdl-19566666

ABSTRACT

BACKGROUND: Hemidesmosomal proteins may become targets of autoimmunity in subepidermal blistering diseases. Well-known recognized autoantigens are the intracellular plaque protein BP230, the transmembrane BP180 and its shed ectodomain LAD-1. OBJECTIVES: To establish the prevalence of autoimmunity against plectin, another intracellular plaque protein, and to investigate its antigenic sites. METHODS: Two hundred and eighty-two patients with subepidermal blistering diseases, investigated by routine immunoblot analysis for possible antiplectin antibodies, were included in the study. Epitope mapping was performed using recombinantly produced overlapping plectin domains from the actin-binding domain to the rod domain. The COOH-terminal region of plectin was not included in the study. RESULTS: In 11 of 282 (3.9%) patients an immunoblot staining pattern identical to that of antiplectin monoclonal antibody HD121 was found. Affinity-purified antibodies bound back to normal human skin in a pattern typical for plectin, i.e. to the epidermal basement membrane zone as well as to keratinocytes in the epidermis, and to myocytes. No binding was seen to plectin-deficient skin of a patient with epidermolysis bullosa simplex with muscular dystrophy. Epitope mapping of the plectin molecule showed that the central coiled-coil rod domain is an immunodominant hotspot as 92% of the sera with antiplectin antibodies reacted with it. Most patients with antiplectin antibodies also had antibodies to other pemphigoid antigens. CONCLUSIONS: Plectin is a minor pemphigoid antigen with an immunodominant epitope located on the central rod domain.


Subject(s)
Autoantibodies/immunology , Immunodominant Epitopes/immunology , Pemphigoid, Bullous/immunology , Plectin/immunology , Adult , Aged , Aged, 80 and over , Autoantigens/immunology , Epitope Mapping , Female , Humans , Immunoblotting , Immunoglobulin A/immunology , Immunoglobulin G/immunology , Infant , Male , Middle Aged
5.
Exp Cell Res ; 314(3): 590-602, 2008 Feb 01.
Article in English | MEDLINE | ID: mdl-18155192

ABSTRACT

The CXC chemokine CXCL12 and its cognate receptor CXCR4 play an important role in inflammation, human immunodeficiency virus (HIV) infection and cancer metastasis. The signal transduction and intracellular trafficking of CXCR4 are involved in these functions, but the underlying mechanisms remain incompletely understood. In the present study, we demonstrated that the CXCR4 formed a complex with the cytolinker protein plectin in a ligand-dependent manner in HEK293 cells stably expressing CXCR4. The glutathione-S-transferase (GST)-CXCR4 C-terminal fusion proteins co-precipitated with the full-length and the N-terminal fragments of plectin isoform 1 but not with the N-terminal deletion mutants of plectin isoform 1, thereby suggesting an interaction between the N-terminus of plectin and the C-terminus of CXCR4. This interaction was confirmed by confocal microscopic reconstructions showing co-distribution of these two proteins in the internal vesicles after ligand-induced internalization of CXCR4 in HEK293 cells stably expressing CXCR4. Knockdown of plectin with RNA interference (RNAi) significantly inhibited ligand-dependent CXCR4 internalization and attenuated CXCR4-mediated intracellular calcium mobilization and activation of extracellular signal regulated kinase 1/2 (ERK1/2). CXCL12-induced chemotaxis of HEK293 cells stably expressing CXCR4 and of Jurkat T cells was inhibited by the plectin RNAi. Moreover, CXCR4 tropic HIV-1 infection in MAGI (HeLa-CD4-LTR-Gal) cells was inhibited by the RNAi of plectin. Thus, plectin appears to interact with CXCR4 and plays an important role in CXCR4 signaling and trafficking and HIV-1 infection.


Subject(s)
HIV Infections/immunology , HIV-1/immunology , Plectin/immunology , Receptors, CXCR4/immunology , Calcium Signaling/genetics , Calcium Signaling/immunology , Cell Line , Chemokine CXCL12/immunology , Chemokine CXCL12/metabolism , Chemotaxis/drug effects , Chemotaxis/genetics , Chemotaxis/immunology , Endocytosis/genetics , Endocytosis/immunology , Extracellular Signal-Regulated MAP Kinases/immunology , Extracellular Signal-Regulated MAP Kinases/metabolism , HIV Infections/metabolism , HIV-1/metabolism , HeLa Cells , Humans , Jurkat Cells , Macromolecular Substances/metabolism , Microscopy, Confocal , Plectin/genetics , Plectin/metabolism , Protein Structure, Tertiary/physiology , Protein Transport/immunology , RNA Interference/immunology , Receptors, CXCR4/metabolism , Recombinant Fusion Proteins/metabolism , Signal Transduction/immunology , Transport Vesicles/immunology , Transport Vesicles/metabolism , Transport Vesicles/ultrastructure , Virus Internalization
6.
J Cell Biol ; 176(7): 965-77, 2007 Mar 26.
Article in English | MEDLINE | ID: mdl-17389230

ABSTRACT

In skeletal muscle, the cytolinker plectin is prominently expressed at Z-disks and the sarcolemma. Alternative splicing of plectin transcripts gives rise to more than eight protein isoforms differing only in small N-terminal sequences (5-180 residues), four of which (plectins 1, 1b, 1d, and 1f) are found at substantial levels in muscle tissue. Using plectin isoform-specific antibodies and isoform expression constructs, we show the differential regulation of plectin isoforms during myotube differentiation and their localization to different compartments of muscle fibers, identifying plectins 1 and 1f as sarcolemma-associated isoforms, whereas plectin 1d localizes exclusively to Z-disks. Coimmunoprecipitation and in vitro binding assays using recombinant protein fragments revealed the direct binding of plectin to dystrophin (utrophin) and beta-dystroglycan, the key components of the dystrophin-glycoprotein complex. We propose a model in which plectin acts as a universal mediator of desmin intermediate filament anchorage at the sarcolemma and Z-disks. It also explains the plectin phenotype observed in dystrophic skeletal muscle of mdx mice and Duchenne muscular dystrophy patients.


Subject(s)
Dystroglycans/metabolism , Muscle Fibers, Skeletal/metabolism , Muscle, Skeletal/metabolism , Muscular Dystrophy, Animal/metabolism , Plectin/metabolism , Sarcolemma/metabolism , Animals , Cell Compartmentation/physiology , Cell Differentiation/physiology , Cells, Cultured , Cytoskeleton/metabolism , Cytoskeleton/ultrastructure , Desmin/metabolism , Humans , Immunohistochemistry , Intermediate Filaments/metabolism , Intermediate Filaments/ultrastructure , Mice , Mice, Inbred C57BL , Mice, Inbred mdx , Models, Biological , Muscle Fibers, Skeletal/pathology , Muscle Fibers, Skeletal/ultrastructure , Muscle, Skeletal/pathology , Muscle, Skeletal/physiopathology , Muscular Dystrophy, Animal/genetics , Muscular Dystrophy, Animal/physiopathology , Plectin/immunology , Protein Isoforms/immunology , Protein Isoforms/metabolism , Rats , Sarcolemma/pathology , Sarcolemma/ultrastructure , Utrophin/metabolism
7.
Clin Exp Dermatol ; 30(5): 531-4, 2005 Sep.
Article in English | MEDLINE | ID: mdl-16045687

ABSTRACT

We present a case of inflammatory epidermolysis bullosa acquisita (EBA) with IgA antibodies to plectin. Analysis of lesional skin biopsies by electron microscopy revealed the split level to be in the sublamina densa zone, corresponding to the diagnosis of EBA. Direct immunofluorescence of perilesional skin demonstrated u-serrated depositions of IgG and IgA that under immunoelectron microscopy were shown to be located in the sublamina densa. In contrast, indirect immunofluorescence on salt-split skin revealed circulating IgA antibodies that stained the roof rather than the floor of the blister. Immunoblotting showed these serum antibodies to be directed to the cytoplasmic hemidesmosomal antigen plectin. The antiplectin specificity of these antibodies was confirmed by 'knockout' immunofluorescence analysis; the serum IgA did not bind to skin sections of a patient with plectin-deficient epidermolysis bullosa. To our knowledge, this case demonstrates for the first time the existence of IgA antibodies against plectin.


Subject(s)
Autoantibodies/analysis , Epidermolysis Bullosa Acquisita/immunology , Immunoglobulin A/analysis , Plectin/immunology , Aged , Epidermolysis Bullosa Acquisita/pathology , Female , Humans , Skin/ultrastructure
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