LEKTI proteolytic processing in human primary keratinocytes, tissue distribution and defective expression in Netherton syndrome
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State: Public
Version: Final published version
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It was possible to publish this article open access thanks to a Swiss National Licence with the publisher.
State: Public
Version: Final published version
License: Not specified
It was possible to publish this article open access thanks to a Swiss National Licence with the publisher.
Serval ID
serval:BIB_4AF9715D475F
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
LEKTI proteolytic processing in human primary keratinocytes, tissue distribution and defective expression in Netherton syndrome
Journal
Human Molecular Genetics
ISSN
0964-6906 (Print)
Publication state
Published
Issued date
10/2003
Volume
12
Number
19
Pages
2417-30
Notes
Journal Article
Research Support, Non-U.S. Gov't --- Old month value: Oct 1
Research Support, Non-U.S. Gov't --- Old month value: Oct 1
Abstract
SPINK5, encoding the putative multi-domain serine protease inhibitor LEKTI, was recently identified as the defective gene in the severe autosomal recessive ichthyosiform skin condition, Netherton syndrome (NS). Using monoclonal and polyclonal antibodies, we show that LEKTI is a marker of epithelial differentiation, strongly expressed in the granular and uppermost spinous layers of the epidermis, and in differentiated layers of stratified epithelia. LEKTI expression was also demonstrated in normal differentiated human primary keratinocytes (HK) through detection of a 145 kDa full-length protein and a shorter isoform of 125 kDa. Both proteins are N-glycosylated and rapidly processed in a post-endoplasmic reticulum compartment into at least three C-terminal fragments of 42, 65 and 68 kDa, also identified in conditioned media. Processing of the 145 and 125 kDa precursors was prevented in HK by treatment with a furin inhibitor. In addition, in vitro cleavage of the recombinant 145 kDa precursor by furin generated C-terminal fragments of 65 and 68 kDa, further supporting the involvement of furin in LEKTI processing. In contrast, LEKTI precursors and proteolytic fragments were not detected in differentiated HK from NS patients. Defective expression of LEKTI in skin sections was a constant feature in NS patients, whilst an extended reactivity pattern was observed in samples from other keratinizing disorders, demonstrating that loss of LEKTI expression in the epidermis is a diagnostic feature of NS. The identification of novel processed forms of LEKTI provides the basis for future functional and structural studies of fragments with physiological relevance.
Keywords
Carrier Proteins/*genetics/*metabolism
Cell Compartmentation
Cell Differentiation
Cells, Cultured
Culture Media, Conditioned/analysis
Endoplasmic Reticulum/metabolism
Furin/antagonists & inhibitors/pharmacology
Gene Expression
Genes, Recessive
Glycosylation
Humans
Ichthyosiform Erythroderma, Congenital/diagnosis/*pathology
Keratinocytes/drug effects/*metabolism
Keratosis/diagnosis/*pathology
Protein Isoforms/genetics/metabolism
Protein Processing, Post-Translational/*drug effects
Syndrome
Tissue Distribution
Pubmed
Web of science
Open Access
Yes
Create date
25/01/2008 17:36
Last modification date
14/02/2022 8:54