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The Journal of Cell Biology Dec 1999We cloned and characterized a full-length cDNA of mouse actin cross-linking family 7 (mACF7) by sequential rapid amplification of cDNA ends-PCR. The completed mACF7 cDNA...
We cloned and characterized a full-length cDNA of mouse actin cross-linking family 7 (mACF7) by sequential rapid amplification of cDNA ends-PCR. The completed mACF7 cDNA is 17 kb and codes for a 608-kD protein. The closest relative of mACF7 is the Drosophila protein Kakapo, which shares similar architecture with mACF7. mACF7 contains a putative actin-binding domain and a plakin-like domain that are highly homologous to dystonin (BPAG1-n) at its NH(2) terminus. However, unlike dystonin, mACF7 does not contain a coiled-coil rod domain; instead, the rod domain of mACF7 is made up of 23 dystrophin-like spectrin repeats. At its COOH terminus, mACF7 contains two putative EF-hand calcium-binding motifs and a segment homologous to the growth arrest-specific protein, Gas2. In this paper, we demonstrate that the NH(2)-terminal actin-binding domain of mACF7 is functional both in vivo and in vitro. More importantly, we found that the COOH-terminal domain of mACF7 interacts with and stabilizes microtubules. In transfected cells full-length mACF7 can associate not only with actin but also with microtubules. Hence, we suggest a modified name: MACF (microtubule actin cross-linking factor). The properties of MACF are consistent with the observation that mutations in kakapo cause disorganization of microtubules in epidermal muscle attachment cells and some sensory neurons.
Topics: Actin Cytoskeleton; Actins; Amino Acid Motifs; Amino Acid Sequence; Animals; COS Cells; Carrier Proteins; Cloning, Molecular; Cytoskeletal Proteins; Cytoskeleton; Drosophila Proteins; Dystonin; Dystrophin; Embryo, Mammalian; Humans; Mice; Microfilament Proteins; Microtubules; Molecular Sequence Data; Nerve Tissue Proteins; Protein Binding; Protein Structure, Secondary; RNA, Messenger; Recombinant Fusion Proteins; Sequence Analysis, DNA; Sequence Homology, Amino Acid
PubMed: 10601340
DOI: 10.1083/jcb.147.6.1275 -
Molecular Biology Reports 1996Ultrastructural examination of the cutaneous basement membrane zone (BMZ) reveals the presence of several attachment structures, which are critical for integrity of the... (Review)
Review
Ultrastructural examination of the cutaneous basement membrane zone (BMZ) reveals the presence of several attachment structures, which are critical for integrity of the stable association of epidermis and dermis. These include hemidesmosomes which extend from the intracellular compartment of the basal keratinocyte to the underlying basement membrane where they complex with anchoring filaments, thread-like structures traversing the lamina lucida. At the lower portion of dermal-epidermal attachment zone, anchoring fibrils extend from the lamina densa to the papillary dermis, where they associate with basement membrane-like structures, known as anchoring plaques. Molecular cloning of the cutaneous BMZ components has allowed elucidation of the structural features of the proteins which constitute these attachment structures. Specifically, hemidesmosomes have been shown to consist of at least four distinct proteins. The intracellular hemidesmosomal inner plaque is comprised of the 230-kD bullous pemphigoid antigen (BPAG1), and plectin, a high-molecular weight cytomatrix protein, encoded by the corresponding gene, PLEC1. The transmembrane component of the hemidesmosomes consists of the 180-kD bullous pemphigoid antigen (BPAG2), a collagenous protein also known as type XVII collagen (COL17A1), as well as of the basal keratinocyte-specific integrin alpha 6 beta 4. The anchoring filaments consist predominantly of laminin 5 with three constitutive subunit polypeptides, the alpha 3, beta 3 and gamma 2 chains, which is associated with laminin 6 with the chain composition alpha 3, beta 1 and gamma 1. Also associated with anchoring filaments is a novel protein, ladinin, which serves as autoantigen in the linear IgA disease, and the corresponding gene, LAD1, has been mapped to human chromosome 1. Finally, the major, if not the exclusive, component of anchoring fibrils is type VII collagen, encoded by the gene (COL7A1) which consists of 118 distinct exons, the largest number of exons in any gene published thus far. Collectively, the cutaneous basement membrane zone is a complex continuum of macromolecules which form a network providing the stable association of the epidermis to the underlying dermis. Thus, genetic lesions resulting in abnormalities in any part of this network could result in a blistering skin disease, such as epidermolysis bullosa.
Topics: Antigens, CD; Autoantigens; Basement Membrane; Carrier Proteins; Collagen; Cytoskeletal Proteins; Desmosomes; Dystonin; Epidermis; Extracellular Matrix Proteins; Genetic Diseases, Inborn; Humans; Integrin alpha6; Integrin beta4; Intermediate Filament Proteins; Laminin; Membrane Glycoproteins; Nerve Tissue Proteins; Non-Fibrillar Collagens; Plectin; Skin; Skin Diseases, Vesiculobullous; Collagen Type XVII
PubMed: 8983017
DOI: 10.1007/BF00357071 -
The Journal of Dermatology Sep 2021IgE autoantibodies targeting BP230 can be identified in 38%-68% of bullous pemphigoid (BP) patients, yet the diagnostic and pathogenic value of anti-BP230 IgE still...
BACKGROUND
IgE autoantibodies targeting BP230 can be identified in 38%-68% of bullous pemphigoid (BP) patients, yet the diagnostic and pathogenic value of anti-BP230 IgE still remains inconclusive.
OBJECTIVE
We intend to investigate the clinical and immunological characteristics of anti-BP230 IgE in BP patients.
METHODS AND RESULTS
Fifty-four BP patients were divided into two groups based on the responsiveness of a topical steroid. We investigated clinical features and IgE autoantibodies profiles by indirect immunofluorescence, ELISA and western blot between the two groups. BP disease area index (BPDAI) scores, total IgE, peripheral eosinophil counts, and anti-BP230 IgE level were significantly higher in the topical-steroid-resistant group. The majority of topical-steroid-resistant patients present with blister/erythematous phenotype (64.3%) and anti-BP230 IgE (59.5%), which correlates with total IgE levels. ELISAs of domain-specific BP230 recombinant proteins indicated that IgE in the topical-steroid-resistant group can react with all seven domains of BP230 and more frequently with the BP230-R1 epitope.
CONCLUSION
Anti-BP230 IgE is more frequently observed in topical-steroid-therapy-resistant patients and the prefers R1 domain of BP230, which is not included in commercially available testing kits. Our study further suggests the pathogenic role of anti-BP230 IgE in BP. Performing anti-BP230 IgE detection can serve as an indicator for initiating systemic steroid therapy.
Topics: Autoantibodies; Autoantigens; Dystonin; Enzyme-Linked Immunosorbent Assay; Humans; Immunoglobulin E; Non-Fibrillar Collagens; Pemphigoid, Bullous; Steroids
PubMed: 34128260
DOI: 10.1111/1346-8138.15952 -
Der Hautarzt; Zeitschrift Fur... Sep 2000Bullous pemphigoid (BP) is a subepidermal blistering autoimmune disease of the elderly. Autoantibodies are directed against two hemidesmosomal proteins, designated BP180... (Review)
Review
Bullous pemphigoid (BP) is a subepidermal blistering autoimmune disease of the elderly. Autoantibodies are directed against two hemidesmosomal proteins, designated BP180 and BP230. While BP230 localizes intracellularly and associates with the hemidesmosomal plaque, BP180 is a transmembrane glycoprotein with an extracellular domain consisting of approximately 1000 amino acids. The non-collagenous (NC) 16A domain, that encompasses 76 amino acids and localizes directly adjacent to the transmembrane region, has been identified as an immunodominant region of the BP180 ectodomain. In the majority of BP sera, circulating antibodies to BP180 NC16A are detected; their serum levels correlate with disease activity. Neonatal mice that are injected with rabbit anti-murine BP180 antibodies develop a BP-like subepidermal blistering disease demonstrating the biological importance of antibodies to BP180. The pathogenically relevant site on murine BP180 corresponds to a stretch of the NC16A domain on human BP180. In contrast to pemphigus, in BP, autoantibodies alone are not sufficient to induce blisters. In addition, complement activation, the infiltration of inflammatory cells and the release of proteases and various inflammatory mediators, including cytokines, are essential for lesion formation. In this review, we give an up-date on the pathogenesis of BP.
Topics: Animals; Animals, Newborn; Autoantibodies; Autoantigens; Carrier Proteins; Collagen; Cytoskeletal Proteins; Dystonin; Humans; Mice; Nerve Tissue Proteins; Non-Fibrillar Collagens; Pemphigoid, Bullous; Rabbits; Skin; Collagen Type XVII
PubMed: 11057389
DOI: 10.1007/s001050051188 -
Annals of the New York Academy of... Dec 1991
Review
Topics: Autoantigens; Carrier Proteins; Collagen; Cytoskeletal Proteins; Dystonin; Extracellular Matrix; Extracellular Matrix Proteins; Fibronectins; Glycosaminoglycans; Hair; Humans; Laminin; Nerve Tissue Proteins; Non-Fibrillar Collagens; Pemphigoid, Bullous; Collagen Type XVII
PubMed: 1809085
DOI: 10.1111/j.1749-6632.1991.tb24392.x -
The Journal of Investigative Dermatology Apr 1999The attachment of cells to the extracellular matrix is of crucial importance in the maintenance of tissue structure and integrity. In stratified epithelia such as in... (Review)
Review
The attachment of cells to the extracellular matrix is of crucial importance in the maintenance of tissue structure and integrity. In stratified epithelia such as in skin as well as in other complex epithelia multiprotein complexes called hemidesmosomes are involved in promoting the adhesion of epithelial cells to the underlying basement membrane. In the past few years our understanding of the role of hemidesmosomes has improved considerably. Their importance has become apparent in clinical conditions, in which absence or defects of hemidesmosomal proteins result in devastating blistering diseases of the skin. Molecular genetic studies have increased our knowledge of the function of the various components of hemidesmosomes and enabled the characterization of protein-protein interactions involved in their assembly. It has become clear that the alpha6beta4 integrin, a major component of hemidesmosomes, is able to transduce signals from the extracellular matrix to the interior of the cell, that critically modulate the organization of the cytoskeleton, proliferation, apoptosis, and differentiation. Nevertheless, our knowledge of the mechanisms regulating the functional state of hemidesmosomes and, hence, the dynamics of cell adhesion, a process of crucial importance in development, wound healing or tumor invasion, remains limited. The aims of this review are to highlight the recent progresses of our knowledge on the organization and assembly of hemidesmosomes, their involvement in signaling pathways as well as their participation in clinical pathologic conditions.
Topics: Animals; Antigens, Surface; Autoantigens; Carrier Proteins; Cell Adhesion; Cell Adhesion Molecules; Collagen; Cytoskeletal Proteins; Desmosomes; Dystonin; Humans; Integrin alpha6beta4; Integrins; Intermediate Filament Proteins; Mice; Mice, Knockout; Nerve Tissue Proteins; Non-Fibrillar Collagens; Plectin; Kalinin; Collagen Type XVII
PubMed: 10201522
DOI: 10.1046/j.1523-1747.1999.00546.x -
Experimental Dermatology Apr 2016
Topics: Animals; Collagen; Dystonin; Epidermolysis Bullosa Simplex; Hemidesmosomes; Hereditary Sensory and Autonomic Neuropathies; Humans; Integrin beta4; Keratinocytes; Mice; Mutation; Plakins; Protein Isoforms; Signal Transduction; Systems Biology
PubMed: 26740080
DOI: 10.1111/exd.12939 -
HLA Mar 2017Bullous pemphigoid (BP) is the most common autoimmune blistering disease and is linked to IgG recognition of 2 hemidesmosomal antigens, that is, BP230 (BP antigen 1) and... (Review)
Review
A multi-hit hypothesis of bullous pemphigoid and associated neurological disease: Is HLA-DQB1*03:01, a potential link between immune privileged antigen exposure and epitope spreading?
Bullous pemphigoid (BP) is the most common autoimmune blistering disease and is linked to IgG recognition of 2 hemidesmosomal antigens, that is, BP230 (BP antigen 1) and BP180 (BP antigen 2, collagen XVII). The association of BP with other systemic diseases, particularly neurocognitive diseases, provides a potential clue in the underlying pathogenesis of BP. The role of HLA-DQB1*03:01 binding to the immunogenic portion of BP180 provides a potential mechanism by which exposure to neuronal collagen BP180 may lead to cutaneous disease. In our proposed multi-hit hypothesis, patients with underlying neuronal disease are exposed to previously sequestered self-antigen, most importantly BP180. Patients with the HLA-DQB1*03:01 allele show an increased T-cell avidity to several epitopes of BP180, particularly the BP180-NC16a domain. Thus, they have a genetic susceptibility to developing BP upon exposure to the target antigen. In a patient with dysregulation of Th1/Th2 balance, anergy is lost and T-cells are subsequently primed resulting in the development of functional autoimmunity against the BP180-NC16a domain leading to clinically overt disease.
Topics: Autoantibodies; Autoantigens; Dystonin; Epitopes; Gene Expression; Genetic Predisposition to Disease; HLA-DQ beta-Chains; Histocompatibility Testing; Humans; Neurodegenerative Diseases; Non-Fibrillar Collagens; Pemphigoid, Bullous; T-Lymphocytes; Collagen Type XVII
PubMed: 28101965
DOI: 10.1111/tan.12960 -
Journal of Dermatological Science Feb 2022Bullous pemphigoid (BP) is the most common autoimmune blistering disease. BP is characterized by the development of tense blisters induced by tissue-bound specific... (Review)
Review
Bullous pemphigoid (BP) patients with selective IgG autoreactivity against BP230: Review of a rare but valuable cohort with impact on the comprehension of the pathogenesis of BP.
Bullous pemphigoid (BP) is the most common autoimmune blistering disease. BP is characterized by the development of tense blisters induced by tissue-bound specific autoantibodies directed against the major autoantigens bullous pemphigoid autoantigen 180 (BP180, also called BPAG2 or Collagen XVII) and bullous pemphigoid autoantigen 230 (BP230, also called BPAG1 or dystonin). The vast majority of BP patients have autoantibodies targeting BP180, or both, BP180 and BP230. The hemidesmosomal protein BP180 is regarded as the main autoantigen, whereas the pathophysiologic relevance of intracellularly-located BP230 is controversial. A small subpopulation of BP patients selectively reveals autoantibodies against BP230 (BP230 patients) strongly supporting that BP230 autoantibodies might be sufficient to induce skin pathology. In line, BP animal models have been developed, which successfully mimic a human BP phenotype by targeting BP230. In this context, our group has recently shown that a murine autoantibody targeting BP230 induces subepidermal blisters in vivo. This finding suggests that blister formation in the population of patients with selective autoreactivity against BP230 may share pathophysiologic features of pathogenic anti-BP230 autoantibodies in our murine model. This review summarizes the clinical features of BP patients with selective autoreactivity against BP230, enlightens the currently available BP mouse models targeting BP230 and discusses the potential pathophysiological mechanism of BP230 autoantibodies.
Topics: Animals; Autoantibodies; Autoantigens; Comprehension; Dystonin; Humans; Immunoglobulin G; Mice; Non-Fibrillar Collagens; Pemphigoid, Bullous; Skin
PubMed: 34930674
DOI: 10.1016/j.jdermsci.2021.11.011 -
The Journal of Dermatology Sep 2019
Review
Topics: Adult; Animals; Antiparasitic Agents; Autoantibodies; Autoantigens; Biopsy; Dystonin; Humans; Immunoglobulin G; Ivermectin; Laminin; Male; Non-Fibrillar Collagens; Pemphigoid, Bullous; Sarcoptes scabiei; Scabies; Serologic Tests; Skin; Treatment Outcome; Collagen Type XVII
PubMed: 30969443
DOI: 10.1111/1346-8138.14883