KLK5 and KLK7 Ablation Fully Rescues Lethality of Netherton Syndrome-Like Phenotype

Kašpárek, Petr; Ileninova, Zuzana; Zbodakova, Olga; Kanchev, Ivan; Benada, Oldřich; Chalupský, Karel; Brattsand, Maria; Beck, Inken M.; Sedláček, Radislav

doi:10.1371/journal.pgen.1006566

Cited by 72 publications

(76 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Specifically, it was shown that persistent inflammation and TSLP production in atopic dermatitis (AD) is induced by KLK5 in a PAR2-independent manner [28]. On the other side, the latter study [28] confirmed that KLK5 plays an important role in DSG1 degradation as has been shown previously [13,24] further substantiating the key role of KLK5 in the desquamation process.…”

Section: Discussionsupporting

confidence: 68%

“…Deletion of Klk6 restored normal epidermal differentiation patterns in Spink5 À/À epidermis. Previously, it was shown that deletion of Klk7 in Spink5 À/À mice did not prevent epidermal overdesquamation but it normalized epidermal differentiation and inflammation [24], suggesting that Klk6 and Klk7 may have common functions in skin. Since KLK7 is not able to activate PAR2 [25] this finding indicates that, probably, there are other yet unknown PAR2-independent pathways that regulate the induction of inflammation by KLKs in the epidermis.…”

Section: Discussionmentioning

confidence: 98%

See 1 more Smart Citation

A proinflammatory role of KLK6 protease in Netherton syndrome

Zingkou

Pampalakis

Charla

et al. 2019

Journal of Dermatological Science

View full text Add to dashboard Cite

Background: Netherton syndrome (NS) is a rare but severe type of ichthyosis characterized by atopy, allergies, and potentially lethal skin overdesquamation associated with highly elevated proteolytic activities in LEKTI-deficient epidermis. NS symptoms are recapitulated in Spink5 À/À mouse where the gene encoding Lekti has been invalidated. Spink5 À/À mice die within 5 h from birth due to their severe skin barrier defect leading to dehydration. Spink5 À/À mice also serve as a model for atopic dermatitis. The KLK6 protease is expressed by epidermal keratinocytes and shown in vitro to cleave desmosomal components. Objective: To investigate in vivo whether KLK6 is implicated in epidermal overdesquamation and/or inflammation associated with NS. Methods: The role of KLK6 was evaluated by generating Spink5 À/À Klk6 À/À double knockout mice. The phenotype was assessed by macroscopic observation, immunohistochemistry for differentiation markers, in situ zymography for proteolysis, and quantification of proinflammatory cytokines. Results: Elimination of Klk6 in Spink5 À/À remarkably suppresses the expression of Tslp, a major itchinginducing factor and driver of allergic reactions. Tnfα and the Th17 promoting cytokine Il-23 were also suppressed. Spink5 À/À Klk6 À/À mice display normalized keratinocyte differentiation, nevertheless, epidermal proteolytic activities and the associated overdesquamation were not ameliorated, and Spink5 À/À Klk6 À/À still died from a severe epidermal barrier defect as the Spink5 À/À. Conclusions: Ablation of Klk6 largely suppresses epidermal inflammation but cannot rescue overdesquamation leading to the lethal NS phenotype. Nonetheless, our findings demonstrate for the first time that KLK6 is implicated in skin inflammation and may represent a novel druggable target for NS and other inflammatory conditions e.g. atopic dermatitis.

show abstract

Section: Discussionsupporting

confidence: 68%

Section: Discussionmentioning

confidence: 98%

A proinflammatory role of KLK6 protease in Netherton syndrome

Zingkou

Pampalakis

Charla

et al. 2019

Journal of Dermatological Science

View full text Add to dashboard Cite

show abstract

“…As shown by Fortugno et al ., LEKTI is processed into different active domains by the enzyme furin . Moreover, there is increasing evidence that it is mainly loss of KLK5 control that drives the phenotype of Netherton syndrome . Now we confirm that the LEKTI domains D6, D7 and D8+9 are active inhibitors of KLK5, and we show that these fragments are substrates for TG1.…”

Section: Discussionsupporting

confidence: 66%

LEKTI domains D6, D7 and D8+9 serve as substrates for transglutaminase 1: implications for targeted therapy of Netherton syndrome

et al. 2019

View full text Add to dashboard Cite

Background Transglutaminase (TG)1 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 increased activity of both TG1 and serin proteases. Objectives To determine 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 and D8+9 were examined in vitro and in situ for possible substrate specificity. The recombinant LEKTI domains were studied for inhibitory activity in a kallikrein (KLK)5 activity test. Results We identified possible TG1 consensus sequences in LEKTI domains D6, D7 and 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 entire recombinant domains of LEKTI showed substrate specificity for TG1, which was again confirmed in situ. The inhibitory activity of the recombinant LEKTI domains was confirmed by a KLK5 inhibition test. The strongest inhibition was observed for domains D8+9. Conclusions There are specific domains of LEKTI that are recognized and processed by TG1. 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.What's already known about this topic?• LEKTI and transglutaminase (TG)1 are key proteins involved in the terminal differentiation of the epidermis.• Lack of LEKTI causes Netherton syndrome; TG1 deficiency causes lamellar ichthyosis.• The serine protease inhibitor LEKTI is processed into different functional units. • Among different target proteases, kallikrein (KLK)5 appears to be a key player in disease pathology.• It has been demonstrated that LEKTI domain 6 inhibits KLK5 and KLK7; LEKTI domains 8-11 also inhibit KLK14.

show abstract

“…NGP (Neutrophilic granule protein) or ‘bectenecin’ – also belongs to cathelicidins, has a cathelicidin protein domain, and in our data, it is also significantly up-regulated in metestrus (2.8 fold), likely because it is co-expressed with CAMP in neutrophils which invade vaginal environment during metestrus. CAMP is regulated by the serine-proteases Kallikreins 5 and 7 55 and thus belongs to an extended KLK/LEKTI network members that are crucial for homeostasis of stratified epithelia 56 . We did not detect KLK5 and KLK7 in the vaginal secretion.…”

Section: Resultsmentioning

confidence: 99%

Differential regulation of vaginal lipocalins (OBP, MUP) during the estrous cycle of the house mouse

Černá

Kuntová

Talacko

et al. 2017

Sci Rep

View full text Add to dashboard Cite

Female house mice produce pheromone-carrying major urinary proteins (MUPs) in a cycling manner, thus reaching the maximum urinary production just before ovulation. This is thought to occur to advertise the time of ovulation via deposited urine marks. This study aimed to characterize the protein content from the house mouse vaginal flushes to detect putative vaginal-advertising molecules for a direct identification of reproductive states. Here we show that the mouse vaginal discharge contains lipocalins including those from the odorant binding (OBP) and major urinary (MUP) protein families. OBPs were highly expressed but only slightly varied throughout the cycle, whilst several MUPs were differentially abundant. MUP20 or ‘darcin’, was thought to be expressed only by males. However, in females it was significantly up-regulated during estrus similarly as the recently duplicated central/group-B MUPs (sMUP17 and highly expressed sMUP9), which in the mouse urine are male biased. MUPs rise between proestrus and estrus, remain steady throughout metestrus, and are co-expressed with antimicrobial proteins. Thus, we suggest that MUPs and potentially also OBPs are important components of female vaginal advertising of the house mouse.

show abstract

KLK5 and KLK7 Ablation Fully Rescues Lethality of Netherton Syndrome-Like Phenotype

Cited by 72 publications

References 48 publications

A proinflammatory role of KLK6 protease in Netherton syndrome

A proinflammatory role of KLK6 protease in Netherton syndrome

LEKTI domains D6, D7 and D8+9 serve as substrates for transglutaminase 1: implications for targeted therapy of Netherton syndrome

Differential regulation of vaginal lipocalins (OBP, MUP) during the estrous cycle of the house mouse

Contact Info

Product

Resources

About