Isolation of SPINK6 in human skin: selective inhibitor of kallikrein-related peptidases.
Kallikrein-related peptidases (KLKs) play a central role in skin desquamation. They are tightly controlled by specific inhibitors, including the lymphoepithelial Kazal-type inhibitor (LEKTI) encoded by SPINK5 and LEKTI-2 encoded by SPINK9. Herein, we identify SPINK6 as a selective inhibitor of KLKs in the skin. Unlike LEKTI but similar to LEKTI-2, SPINK6 possesses only one typical Kazal domain. Its mRNA was detected to be expressed at low levels in several tissues and was induced during keratinocyte differentiation. Natural SPINK6 was purified from human plantar stratum corneum extracts. Immunohistochemical analyses revealed SPINK6 expression in the stratum granulosum of human skin at various anatomical localizations and in the skin appendages, including sebaceous glands and sweat glands. SPINK6 expression was decreased in lesions of atopic dermatitis. Using KLK5, KLK7, KLK8, KLK14, thrombin, trypsin, plasmin, matriptase, prostasin, mast cell chymase, cathepsin G, neutrophil elastase, and chymotrypsin, inhibition with recombinant SPINK6 was detected only for KLK5, KLK7, and KLK14, with apparent K(i) values of 1.33, 1070, and 0.5 nm, respectively. SPINK6 inhibited desquamation of human plantar callus in an ex vivo model. Our findings suggest that SPINK6 plays a role in modulating the activity of KLKs in human skin. A selective inhibition of KLKs by SPINK6 might have therapeutic potential when KLK activity is elevated.
Meyer-Hoffert
Ulf
U
Department of Dermatology, University Hospital Schleswig-Holstein, D-24105 Kiel, Germany.
Wu
Zhihong
Z
Kantyka
Tomasz
T
Fischer
Jan
J
Latendorf
Ties
T
Hansmann
Britta
B
Bartels
Joachim
J
He
Yinghong
Y
Gläser
Regine
R
Schröder
Jens-Michael
JM
D000595:Amino Acid Sequence; D001483:Base Sequence; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000302:isolation & purification* / Q000378:metabolism*; D007610:Kallikreins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008969:Molecular Sequence Data; D011480:Protease Inhibitors / Q000302:isolation & purification / Q000378:metabolism; D053491:Proteinase Inhibitory Proteins, Secretory / Q000235:genetics / Q000302:isolation & purification* / Q000378:metabolism*; D016415:Sequence Alignment; D012697:Serine Endopeptidases / Q000378:metabolism*; D000074162:Serine Peptidase Inhibitors, Kazal Type; D012867:Skin / Q000033:anatomy & histology / Q000378:metabolism*; D012871:Skin Diseases / Q000378:metabolism / Q000473:pathology; D014018:Tissue Distribution
D007527:Isoenzymes; D011480:Protease Inhibitors; D053491:Proteinase Inhibitory Proteins, Secretory; C553928:SPINK6 protein, human; D000074162:Serine Peptidase Inhibitors, Kazal Type; D007610:Kallikreins; D012697:Serine Endopeptidases