J. Cell Biol., Volume 142, Number 1, July 13, 1998 271-284

Hemidesmosome Formation Is Initiated by the 4 Integrin Subunit, Requires Complex Formation of 4 and HD1/Plectin, and Involves a Direct Interaction between 4 and the Bullous Pemphigoid Antigen 180 

Roel Q.J. Schaapveld,^* Luca Borradori,^* Dirk Geerts,^* Manuel R. van Leusden,^* Ingrid Kuikman,^* Mirjam G. Nievers,^* Carien M. Niessen,^* Renske D.M. Steenbergen,^§ Peter J.F. Snijders,^§ and Arnoud Sonnenberg^*

^* Division of Cell Biology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands;  Department of Dermatology, University of Geneva, CH-1211 Geneva, Switzerland; and ^§ Department of Pathology, University Hospital Vrije Universiteit, 1081 HV Amsterdam, The Netherlands

Hemidesmosomes (HDs) are stable anchoring structures that mediate the link between the intermediate filament cytoskeleton and the cell substratum. We investigated the contribution of various segments of the 4 integrin cytoplasmic domain in the formation of HDs in transient transfection studies using immortalized keratinocytes derived from an epidermolysis bullosa patient deficient in 4 expression. We found that the expression of wild-type 4 restored the ability of the 4-deficient cells to form HDs and that distinct domains in the NH₂- and COOH-terminal regions of the 4 cytoplasmic domain are required for the localization of HD1/plectin and the bullous pemphigoid antigens 180 (BP180) and 230 (BP230) in these HDs. The tyrosine activation motif located in the connecting segment (CS) of the 4 cytoplasmic domain was dispensable for HD formation, although it may be involved in the efficient localization of BP180. Using the yeast two-hybrid system, we could demonstrate a direct interaction between 4 and BP180 which involves sequences within the COOH-terminal part of the CS and the third fibronectin type III (FNIII) repeat. Immunoprecipitation studies using COS-7 cells transfected with cDNAs for 6 and 4 and a mutant BP180 which lacks the collagenous extracellular domain confirmed the interaction of 4 with BP180. Nevertheless, 4 mutants which contained the BP180-binding region, but lacked sequences required for the localization of HD1/plectin, failed to localize BP180 in HDs. Additional yeast two- hybrid assays indicated that the 85 COOH-terminal residues of 4 can interact with the first NH₂-terminal pair of FNIII repeats and the CS, suggesting that the cytoplasmic domain of 4 is folded back upon itself. Unfolding of the cytoplasmic domain may be part of a mechanism by which the interaction of 4 with other hemidesmosomal components, e.g., BP180, is regulated.

hemidesmosome assembly;  PA-JEB keratinocytes;  protein-protein interaction;  bullous pemphigoid antigens;  64 integrin

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