The differentiation-dependent desmosomal cadherin desmoglein 1 is a novel caspase-3 target that regulates apoptosis in keratinocytes.
Although a number of cell adhesion proteins have been identified as caspase substrates, the potential role of differentiation-specific desmosomal cadherins during apoptosis has not been examined. Here, we demonstrate that UV-induced caspase cleavage of the human desmoglein 1 cytoplasmic tail results in distinct 17- and 140- kDa products, whereas metalloproteinase-dependent shedding of the extracellular adhesion domain generates a 75-kDa product. In vitro studies identify caspase-3 as the preferred enzyme that cleaves desmoglein 1 within its unique repeating unit domain at aspartic acid 888, part of a consensus sequence not conserved among the other desmosomal cadherins. Apoptotic processing leads to decreased cell surface expression of desmoglein 1 and re-localization of its C terminus diffusely throughout the cytoplasm over a time course comparable with the processing of other desmosomal proteins and cytoplasmic keratins. Importantly, whereas classic cadherins have been reported to promote cell survival, short hairpin RNA-mediated suppression of desmoglein 1 in differentiated keratinocytes protected cells from UV-induced apoptosis. Collectively, our results identify desmoglein 1 as a novel caspase and metalloproteinase substrate whose cleavage likely contributes to the dismantling of desmosomes during keratinocyte apoptosis and also reveal desmoglein 1 as a previously unrecognized regulator of apoptosis in keratinocytes.
Dusek
Rachel L
RL
Department of Pathology and Dermatology and Cell Death Regulation Laboratory, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
Getsios
Spiro
S
Chen
Feng
F
Park
Jung K
JK
Amargo
Evangeline V
EV
Cryns
Vincent L
VL
Green
Kathleen J
KJ
D017209:Apoptosis; D001665:Binding Sites; D015153:Blotting, Western; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D003593:Cytoplasm / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D051183:Desmoglein 1 / Q000378:metabolism / Q000502:physiology*; D003896:Desmosomes / Q000378:metabolism; D004318:Doxycycline / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D015603:Keratinocytes / Q000201:enzymology* / Q000378:metabolism; D008856:Microscopy, Fluorescence; D009154:Mutation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012313:RNA / Q000737:chemistry; D012190:Retroviridae / Q000235:genetics; D013997:Time Factors; D014162:Transfection; D014466:Ultraviolet Rays
D018076:DNA, Complementary; D051183:Desmoglein 1; D007211:Indoles; C007293:DAPI; D012313:RNA; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D004318:Doxycycline