LEKTI domains 6, 7 and 8+9 serve as substrates for transglutaminase 1: implications for targeted therapy of Netherton syndrome

Abstract

Background

Transglutaminase 1 (TG1) plays a key role in the formation of the cornified envelope and thus in the maintenance of the epidermal barrier. Patients with Netherton syndrome (LEKTI deficiency) have an increased activity of TG1 as well as of serin proteases.

Objective

We wondered whether there is a functional biochemical link between TG1 and LEKTI and whether LEKTI domains could possibly serve as substrates for TG1.

Methods

We analysed the protein sequence of LEKTI for possible TG1 recognition sites using bioinformatics. Synthetic peptides and recombinant LEKTI domains D6, D7, D8+9 were examined in‐vitro and in‐situ for possible substrate specificity. The recombinant LEKTI domains were studied for inhibitory activity in a KLK5 activity test.

Results

We identified possible TG1 consensus sequences in LEKTI domains D6, D7, D8+9 pointing to a novel biological link between these two proteins. Indeed, synthesized short peptides from these consensus sequences were incorporated into the TG1 activity zone of the epidermis. In‐vitro the recombinant entire domains of LEKTI showed substrate‐specificity for TG1, which could again be confirmed in‐situ. The inhibitory activity of the recombinant LEKTI domains was confirmed by a KLK5 inhibition test. The strongest inhibition was observed for domain D8+D9.

Conclusion

There are specific domains of LEKTI, which are recognized and processed by transglutaminase 1. LEKTI domains D6, D7 and D8+9 contribute to the formation and protection of the cornified envelope. These results impact the development of protein replacement therapy approaches for Netherton syndrome.

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