Proteolytic activation cascade of the Netherton syndrome-defective protein, LEKTI, in the epidermis: implications for skin homeostasis

J Invest Dermatol. 2011 Nov;131(11):2223-32. doi: 10.1038/jid.2011.174. Epub 2011 Jun 23.


Lympho-epithelial Kazal-type-related inhibitor (LEKTI) is the defective protein of the ichthyosiform condition Netherton syndrome (NS). Strongly expressed in the most differentiated epidermal layers, LEKTI is a serine protease inhibitor synthesized as three different high-molecular-weight precursors, which are rapidly processed into shorter fragments and secreted extracellularly. LEKTI polypeptides interact with several proteases to regulate skin barrier homeostasis as well as inflammatory and/or immunoallergic responses. Here, by combining antibody mapping, N-terminal sequencing, and site-specific mutagenesis, we defined the amino-acid sequence of most of the LEKTI polypeptides physiologically generated in human epidermis. We also identified three processing intermediates not described so far. Hence, a proteolytic cascade model for LEKTI activation is proposed. We then pinpointed the most effective fragments against the desquamation-related kallikreins (KLKs) and we proved that LEKTI is involved in stratum corneum shedding as some of its polypeptides inhibit the KLK-mediated proteolysis of desmoglein-1. Finally, we quantified the individual LEKTI fragments in the uppermost epidermis, showing that the ratios between LEKTI polypeptides and active KLK5 are compatible with a fine-tuned inhibition. These findings are relevant both to the understanding of skin homeostasis regulation and to the design of novel therapeutic strategies for NS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Biopsy
  • Case-Control Studies
  • Cells, Cultured
  • Desmoglein 1 / metabolism
  • Epidermis / metabolism*
  • Epidermis / pathology
  • HEK293 Cells
  • Homeostasis / physiology*
  • Humans
  • Kallikreins / metabolism
  • Netherton Syndrome / metabolism*
  • Proteinase Inhibitory Proteins, Secretory / metabolism*
  • Proteolysis*
  • Serine Peptidase Inhibitor Kazal-Type 5
  • Skin / metabolism*
  • Skin / pathology
  • Transfection


  • Desmoglein 1
  • Proteinase Inhibitory Proteins, Secretory
  • SPINK5 protein, human
  • Serine Peptidase Inhibitor Kazal-Type 5
  • Kallikreins