title: LEKTI is localized in lamellar granules, separated from KLK5 and KLK7, and is secreted in the extracellular spaces of the superficial stratum granulosum.
abstract: Lympho-epithelial Kazal-type-related inhibitor (LEKTI) is a putative serine protease inhibitor encoded by serine protease inhibitor Kazal-type 5 (SPINK5). It is strongly expressed in differentiated keratinocytes in normal skin but expression is markedly reduced or absent in Netherton syndrome (NS), a severe ichthyosis caused by SPINK5 mutations. At present, however, both the precise intracellular localization and biological roles of LEKTI are not known. To understand the functional role of LEKTI, we examined the localization of LEKTI together with kallikrein (KLK)7 and KLK5, possible targets of LEKTI, in the human epidermis, by confocal laser scanning microscopy and immunoelectron microscopy. In normal skin, LEKTI, KLK7, and KLK5 were all found in the lamellar granule (LG) system, but were separately localized. LEKTI was expressed earlier than KLK7 and KLK5. In NS skin, LEKTI was absent and an abnormal split in the superficial stratum granulosum was seen in three of four cases. Collectively, these results suggest that in normal skin the LG system transports and secretes LEKTI earlier than KLK7 and KLK5 preventing premature loss of stratum corneum integrity/cohesion. Our data provide new insights into the biological functions of LG and the pathogenesis of NS.
authors.affiliation: Department of Dermatology, Asahikawa Medical College, Midorigaoka-Higashi 2-1-1-1, Asahikawa 078-8510, Japan. akemi@asahikawa-med.ac.jp
authors.forename: Akemi
authors.initials: A
authors.lastname: Ishida-Yamamoto
authors.forename: Céline
authors.initials: C
authors.lastname: Deraison
authors.forename: Chrystelle
authors.initials: C
authors.lastname: Bonnart
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Bitoun
authors.forename: Ross
authors.initials: R
authors.lastname: Robinson
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: O'Brien
authors.forename: Kotaro
authors.initials: K
authors.lastname: Wakamatsu
authors.forename: Sawa
authors.initials: S
authors.lastname: Ohtsubo
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Takahashi
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Hashimoto
authors.forename: Patricia J C
authors.initials: PJ
authors.lastname: Dopping-Hepenstal
authors.forename: John A
authors.initials: JA
authors.lastname: McGrath
authors.forename: Hajime
authors.initials: H
authors.lastname: Iizuka
authors.forename: Gabriele
authors.initials: G
authors.lastname: Richard
authors.forename: Alain
authors.initials: A
authors.lastname: Hovnanian
mesh_terms: D000293:Adolescent; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D003896:Desmosomes / Q000201:enzymology / Q000473:pathology / Q000648:ultrastructure; D004817:Epidermis / Q000378:metabolism / Q000473:pathology; D005110:Extracellular Space / Q000378:metabolism; D005260:Female; D006801:Humans; D007057:Ichthyosis / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D007610:Kallikreins; D015603:Keratinocytes / Q000201:enzymology / Q000473:pathology; D046529:Microscopy, Electron, Transmission; D053491:Proteinase Inhibitory Proteins, Secretory; D012697:Serine Endopeptidases / Q000378:metabolism*; D000074163:Serine Peptidase Inhibitor Kazal-Type 5
chemical_list: D002352:Carrier Proteins; D053491:Proteinase Inhibitory Proteins, Secretory; C120650:SPINK5 protein, human; D000074163:Serine Peptidase Inhibitor Kazal-Type 5; C400147:KLK5 protein, human; C082472:KLK7 protein, human; D007610:Kallikreins; D012697:Serine Endopeptidases