期刊
JOURNAL OF CELL BIOLOGY
卷 153, 期 4, 页码 823-834出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.153.4.823
关键词
catenins; desmosomes; mouse keratinocytes; epithelial differentiation; blistering disease
类别
In pemphigus vulgaris (PV), autoantibody binding to desmoglein (Dsg) 3 induces loss of intercellular adhesion in skin and mucous membranes. Two hypotheses are currently favored to explain the underlying molecular mechanisms: (a) disruption of adhesion through steric hindrance, and (b) interference of desmosomal cadherin-bound antibody with intracellular events, which we speculated to involve plakoglobin. To investigate the second hypothesis we established keratinocyte cultures from plakoglobin knockout (PG(-/-)) embryos and PG(+/+) control mice. Although both cell types exhibited desmosomal cadherin-mediated adhesion during calcium-induced differentiation and bound PV immunoglobin (IgG) at their cell surface, only PG(+/+) keratinocytes responded with keratin retraction and loss of adhesion. When full-length plakoglobin was reintroduced into PG(-/-) cells, responsiveness to PV IgG was restored. Moreover, in these cells Pike in PG(+/+) keratinocytes, PV IgG binding severely affected the linear distribution of plakoglobin at the plasma membrane. Taken together, the establishment of an in vitro model using PG(+/+) and PG(-/-) keratinocytes allowed us (a) to exclude the steric hindrance only hypothesis, and (b) to demonstrate for the first time that plakoglobin plays a central role in PV, a finding that will provide a novel direction for investigations of the molecular mechanisms leading to PV, and on the function of plakoglobin in differentiating keratinocytes.
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