Spink5-deficient mice mimic Netherton syndrome through degradation of desmoglein 1 by epidermal protease hyperactivity.
Mutations in SPINK5, encoding the serine protease inhibitor LEKTI, cause Netherton syndrome, a severe autosomal recessive genodermatosis. Spink5(-/-) mice faithfully replicate key features of Netherton syndrome, including altered desquamation, impaired keratinization, hair malformation and a skin barrier defect. LEKTI deficiency causes abnormal desmosome cleavage in the upper granular layer through degradation of desmoglein 1 due to stratum corneum tryptic enzyme and stratum corneum chymotryptic enzyme-like hyperactivity. This leads to defective stratum corneum adhesion and resultant loss of skin barrier function. Profilaggrin processing is increased and implicates LEKTI in the cornification process. This work identifies LEKTI as a key regulator of epidermal protease activity and degradation of desmoglein 1 as the primary pathogenic event in Netherton syndrome.
Descargues
Pascal
P
INSERM U563, Paul Sabatier University, Place du Dr Baylac, 31059 Toulouse, cedex 3, France.
Deraison
Céline
C
Bonnart
Chrystelle
C
Kreft
Maaike
M
Kishibe
Mari
M
Ishida-Yamamoto
Akemi
A
Elias
Peter
P
Barrandon
Yann
Y
Zambruno
Giovanna
G
Sonnenberg
Arnoud
A
Hovnanian
Alain
A
D000818:Animals; D015820:Cadherins / Q000378:metabolism*; D051183:Desmoglein 1; D004817:Epidermis / Q000473:pathology / Q000648:ultrastructure; D007610:Kallikreins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D012697:Serine Endopeptidases / Q000378:metabolism*; D000074163:Serine Peptidase Inhibitor Kazal-Type 5; D015842:Serine Proteinase Inhibitors / Q000235:genetics* / Q000378:metabolism; D015843:Serpins / Q000235:genetics* / Q000378:metabolism; D012873:Skin Diseases, Genetic / Q000378:metabolism* / Q000473:pathology
D015820:Cadherins; D051183:Desmoglein 1; D000074163:Serine Peptidase Inhibitor Kazal-Type 5; D015842:Serine Proteinase Inhibitors; D015843:Serpins; C495972:Spink5 protein, mouse; D007610:Kallikreins; C495973:Klk5 protein, mouse; C495974:Klk7 protein, mouse; D012697:Serine Endopeptidases