Serum autoantibodies against the extracellular region of α6β4 integrin in a patient with DPP-4 inhibitor-induced bullous pemphigoid

α6β4 integrin, a component of hemidesmosomes, also plays a role in keratinocyte migration via signaling through Rac1 to the actin-severing protein cofilin. Here, we tested the hypothesis that the β4 integrin-associated plakin protein, bullous pemphigoid antigen 1e (BPAG1e) functions as a scaffold for Rac1/cofilin signal transduction. We generated keratinocyte lines exhibiting a stable knockdown in BPAG1e expression. Knockdown of BPAG1e does not affect expression levels of other hemidesmosomal proteins, nor the amount of β4 integrin expressed at the cell surface. However, the amount of Rac1 associating with β4 integrin and the activity of both Rac1 and cofilin are significantly lower in BPAG1e-deficient cells compared with wild-type keratinocytes. In addition, keratinocytes deficient in BPAG1e exhibit loss of front-to-rear polarity and display aberrant motility. These defects are rescued by inducing expression of constitutively active Rac1 or active cofilin. These data indicate that the BPAG1e is required for efficient regulation of keratinocyte polarity and migration by determining the activation of Rac1.

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Redistribution of the Hemidesmosome Components α6β4 Integrin and Bullous Pemphigoid Antigens during Epithelial Wound Healing

Experimental Cell Research ◽

10.1006/excr.1993.1166 ◽

1993 ◽

Vol 207 (1) ◽

pp. 86-98 ◽

Cited By ~ 54

Author(s):

Ilene K. Gipson ◽

Sandra Spurr-Michaud ◽

Ann Tisdale ◽

Jennifer Elwell ◽

Mary Ann Stepp

Keyword(s):

Wound Healing ◽

Bullous Pemphigoid ◽

Epithelial Wound Healing ◽

Α6β4 Integrin

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Expression of the α6β4 Integrin in Lesional Skin Differentiates Bullous Pemphigoid (BP) from Epidermolysis Bullosa Acquisita (EBA)

Journal of Investigative Dermatology ◽

10.1111/1523-1747.ep12555875 ◽

1992 ◽

Vol 98 (2) ◽

pp. 204-208 ◽

Cited By ~ 12

Author(s):

Hélène Michalaki ◽

Marie-Jeanne Staquet ◽

Amilcare Cerri ◽

Emilio Berti ◽

Pascale Roche ◽

...

Keyword(s):

Bullous Pemphigoid ◽

Epidermolysis Bullosa ◽

Epidermolysis Bullosa Acquisita ◽

Lesional Skin ◽

Α6β4 Integrin

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The N Terminus of the Transmembrane Protein BP180 Interacts with the N-terminal Domain of BP230, Thereby Mediating Keratin Cytoskeleton Anchorage to the Cell Surface at the Site of the Hemidesmosome

Molecular Biology of the Cell ◽

10.1091/mbc.11.1.277 ◽

2000 ◽

Vol 11 (1) ◽

pp. 277-286 ◽

Cited By ~ 81

Author(s):

Susan B. Hopkinson ◽

Jonathan C. R. Jones

Keyword(s):

Cell Surface ◽

Bullous Pemphigoid ◽

Transmembrane Protein ◽

Terminal Fragment ◽

C Terminus ◽

N Terminus ◽

Α6β4 Integrin ◽

Two Hybrid ◽

Insight Into

In epidermal cells, the keratin cytoskeleton interacts with the elements in the basement membrane via a multimolecular junction called the hemidesmosome. A major component of the hemidesmosome plaque is the 230-kDa bullous pemphigoid autoantigen (BP230/BPAG1), which connects directly to the keratin-containing intermediate filaments of the cytoskeleton via its C terminus. A second bullous pemphigoid antigen of 180 kDa (BP180/BPAG2) is a type II transmembrane component of the hemidesmosome. Using yeast two-hybrid technology and recombinant proteins, we show that an N-terminal fragment of BP230 can bind directly to an N-terminal fragment of BP180. We have also explored the consequences of expression of the BP230 N terminus in 804G cells that assemble hemidesmosomes in vitro. Unexpectedly, this fragment disrupts the distribution of BP180 in transfected cells but has no apparent impact on the organization of endogenous BP230 and α6β4 integrin. We propose that the BP230 N terminus competes with endogenous BP230 protein for BP180 binding and inhibits incorporation of BP180 into the cell surface at the site of the hemidesmosome. These data provide new insight into those interactions of the molecules of the hemidesmosome that are necessary for its function in integrating epithelial and connective tissue types.

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