Elevated Stratum Corneum Hydrolytic Activity in Netherton Syndrome Suggests an Inhibitory Regulation of Desquamation by SPINK5-Derived Peptides Nahoko.

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Elevated Stratum Corneum Hydrolytic Activity in Netherton Syndrome Suggests an Inhibitory Regulation of Desquamation by SPINK5-Derived Peptides Nahoko Komatsu, Minoru Takata, Norio Otsuki, Rie Ohka, Osamu Amano, Kazuhiko Takehara, Kiyofumi Saijoh Journal of Investigative Dermatology Volume 118, Issue 3, Pages 436-443 (March 2002) DOI: 10.1046/j.0022-202x.2001.01663.x Copyright © 2002 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Clinical features of NS patients from two unrelated Japanese families. (a) Severe erythroderma covered with a collodion-like membrane in the male patient of family A at 2 mo of age. (b) A much milder cutaneous phenotype with patchy islands of normal skin in the family B patient. Journal of Investigative Dermatology 2002 118, 436-443DOI: (10.1046/j.0022-202x.2001.01663.x) Copyright © 2002 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Mutations of the SPINK5 gene identified in two NS families. The genomic sequences of sense strands and the corresponding amino acid sequences are shown at the top of each chart. Asterisks indicate stop codons. The underlined nucleotides are mutated. (a) The siblings in family A are compound heterozygotes of two novel non-sense mutations; a two-nucleotide deletion (375delAT) in exon 5 directly leading to a stop codon at codon 126 (Y126X) and a point mutation from 1621G to T in exon18 resulting in a stop codon (E541X). The Y126X mutant allele was inherited from the heterozygous father, whereas the mother was a E541X heterozygote. (b) The patient in family B was homozygous for a C to T point mutation at nucleotide 2368 in exon 25 generating a stop codon at codon 790 (R790X). This mutation was present in the heterozygous state in both parents. Journal of Investigative Dermatology 2002 118, 436-443DOI: (10.1046/j.0022-202x.2001.01663.x) Copyright © 2002 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 The mRNA expression of carboxypeptidases in normal skin and cultured keratinocytes. 1.0% agarose gel electrophoresis showing amplified products for CPD (761 bp), CPE (511 bp), and GAPDH (351 bp) are visible. Mk is a 100 bp ladder. Journal of Investigative Dermatology 2002 118, 436-443DOI: (10.1046/j.0022-202x.2001.01663.x) Copyright © 2002 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 In situ hybridization for SPINK5 mRNA in normal skin. Anti-sense (top and bottom left) and sense (bottom right) cRNA probes were hybridized to normal skin tissue. The anti-sense probe alone hybridized to the uppermost stratum spinosum and stratum granulosum of the epidermis as well as in hair follicles (top, × 40; bottom left and right, × 200). Journal of Investigative Dermatology 2002 118, 436-443DOI: (10.1046/j.0022-202x.2001.01663.x) Copyright © 2002 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 5 Trypsin-like hydrolytic activity in the stratum corneum samples from NS patients and normal control subjects. The hydrolysis of normal controls indicated as the mean ± SD (n = 10) (○–○) was gradually increased in a time-dependent manner. The SD for 20–60 min was smaller than the size of circles. The hydrolytic activity of patients was indicated as the mean ± SEM of triplicated assay, whereas SEM were within the size of symbols. *p < 0.01; the value was significantly different from the mean of normal controls (Smirnov test for extreme value). The hydrolytic activity of siblings in family A (●–● and ■–■) was about 5-fold higher than those of controls even at 20 min. The hydrolysis of the daughter (●) reached a plateau at 120 min and that of the son (■) at 180 min, both being 66.5 nmol AMC per 1 mg dry weight. The activity of the family B patient (▲–▲) was only slightly higher than those of controls within 60 min but 39.4 nmol AMC per 1 mg dry weight was hydrolyzed at 180 min, being more than twice as much as those of controls. Journal of Investigative Dermatology 2002 118, 436-443DOI: (10.1046/j.0022-202x.2001.01663.x) Copyright © 2002 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 6 Reorganized amino acid sequences of SPINK5 modified from Magert et al (Magert et al, 1999) emphasizing potential SPC cleavage sites. A signal peptide (pink letters in small size), There are a total of 15 serine-protease-inhibitory domains containing Cys–Cys bound loops in the proprotein. Thirteen domains are non Kazal-type with four cysteins (a, b, light brown boxes) and the remaining two are Kazal-type with six cysteins (a, b, yellow boxes), which are encoded by odd number exons (from exon 3 to exon 31). Kazal-type domains (yellow boxes) are also encoded in part by exon 6 and exon 32. This SPINK5 proprotein is suggested to be further processed because there are a number of consensus sequences for possible cleavage sites by SPC (K/R-Xn-K/R ↓ where X is any amino acid and n = 0, 2, 4, or 6; marked in red). R-Xn-KR ↓ is the most potent consensus sequence for furin, which is known to be expressed in the stratum granulosum of the skin (Bergeron et al, 2000). These potential cleavage sites (a, ↓; b, red letters) are encoded by even number exons. A putative cleavage site cannot be found between the second and third domains, and, thus, the SPINK5 proprotein is suggested to be cleaved into at least 14 polypeptides. The basic amino acids at the C-terminal of the cleaved polypeptides are further removed by carboxypeptidases and activated as serine protease inhibitors. Although the activation mechanism for the Kazal-type domain is yet unknown, cleavage by SPC alone appears to be sufficient for activation because SPINK1 with Kazal-type domains are known to be activated by single cleavage (Witt et al, 2000). The peptides indicated in underlined blue letters (b) were isolated from human blood filtrate, and one was shown to have an inhibitory effect on trypsin (Magert et al, 1999). Journal of Investigative Dermatology 2002 118, 436-443DOI: (10.1046/j.0022-202x.2001.01663.x) Copyright © 2002 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 7 A model for desquamation regulation by the SPINK5 proprotein in normal individuals and NS patients. (a) In normal skin, the first cleavage of SPINK5-propotein is carried out at the Lys/Arg (K/R)-Xn-Lys/Ser (K/R) (n = 0, 2, 4, and 6) motif by a cocktail of SPC expressed in keratinocytes. Cleaved peptides are further processed by carboxypeptidases, and a number of peptides with activated Cys–Cys inhibitory domains are generated. These bioactive peptides are inhibitors of stratum corneum serine proteases such as SCTE and SCCE that may degrade intercellular desmoglein-1 and desquamate superficial corneocytes. (b) In NS patients, translation termination mutations in the SPINK5 gene result in the production of truncated proprotein containing fewer inhibitory domains. This leads to the overactivation of stratum corneum serine proteases, overdegradation of desmoglein-1, and finally overdesquamation of corneocytes. Journal of Investigative Dermatology 2002 118, 436-443DOI: (10.1046/j.0022-202x.2001.01663.x) Copyright © 2002 The Society for Investigative Dermatology, Inc Terms and Conditions