Universität zu Köln

Zeeuwen, Patrick L. J. M., van Vlijmen-Willems, Ivonne M. J. J., Cheng, Tsing ORCID: 0000-0001-5191-3289, Rodijk-Olthuis, Diana, Hitomi, Kiyotaka, Hara-Nishimura, Ikuko, John, Susan, Smyth, Neil ORCID: 0000-0002-3734-2149, Reinheckel, Thomas ORCID: 0000-0001-9866-9105, Hendriks, Wiljan J. A. J. and Schalkwijk, Joost ORCID: 0000-0002-1308-1319 (2010). The cystatin M/E-cathepsin L balance is essential for tissue homeostasis in epidermis, hair follicles, and cornea. Faseb J., 24 (10). S. 3744 - 3756. BETHESDA: FEDERATION AMER SOC EXP BIOL. ISSN 0892-6638

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Abstract

Cystatin M/E (CST6) is a nonredundant, epithelium-specific protease inhibitor with a presumed role in epidermal differentiation and tumor suppression. We have previously reported that cystatin M/E deficiency in Cst6(-/-) mice causes neonatal lethality because of excessive transepidermal water loss. Biochemical evidence suggests that cystatin M/E controls the activity of legumain, cathepsin L, cathepsin V, and transglutaminase-3. Using a genetic approach we sought to define the role of cystatin M/E in epithelial biology by identification of its target proteases and their downstream functions. Ablation of cathepsin L in a Cst6(-/-) background (Cst6(-/-) Ctsl(-/-) double-knockout mice) restored viability and resulted in normalization of stratum corneum morphology. Ablation of legumain or transglutaminase-3 in Cst6(-/-) mice, however, did not rescue the lethal phenotype. Intriguingly, both Cst6(-/-) Ctsl(-/-) and Cst6(-/-) Ctsl(+/-) mice were viable, but the absence of cystatin M/E caused scarring alopecia in adult animals. In the cornea of Cst6(-/-) Ctsl(+/-) mice, we observed keratitis, hyperplasia, and transition to a cornified epithelium. Evidence is provided that activation of cathepsin D and transglutaminase-1 are downstream events, dependent of cathepsin L activity. We conclude that a tightly regulated balance between cathepsin L and cystatin M/E is essential for tissue integrity in epidermis, hair follicles, and corneal epithelium.-Zeeuwen, P. L. J. M., van Vlijmen-Willems, I. M. J. J., Cheng, T., Rodijk-Olthuis, D., Hitomi, K., Hara-Nishimura, I., John, S., Smyth, N., Reinheckel, T., Hendriks, W. J. A. J., Schalkwijk, J. The cystatin M/E-cathepsin L balance is essential for tissue homeostasis in epidermis, hair follicles and cornea. FASEB J. 24, 3744-3755 (2010). www.fasebj.org

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Zeeuwen, Patrick L. J. M. UNSPECIFIED UNSPECIFIED UNSPECIFIED van Vlijmen-Willems, Ivonne M. J. J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Cheng, Tsing UNSPECIFIED orcid.org/0000-0001-5191-3289 UNSPECIFIED Rodijk-Olthuis, Diana UNSPECIFIED UNSPECIFIED UNSPECIFIED Hitomi, Kiyotaka UNSPECIFIED UNSPECIFIED UNSPECIFIED Hara-Nishimura, Ikuko UNSPECIFIED UNSPECIFIED UNSPECIFIED John, Susan UNSPECIFIED UNSPECIFIED UNSPECIFIED Smyth, Neil UNSPECIFIED orcid.org/0000-0002-3734-2149 UNSPECIFIED Reinheckel, Thomas UNSPECIFIED orcid.org/0000-0001-9866-9105 UNSPECIFIED Hendriks, Wiljan J. A. J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schalkwijk, Joost UNSPECIFIED orcid.org/0000-0002-1308-1319 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-495507
DOI:	10.1096/fj.10-155879
Journal or Publication Title:	Faseb J.
Volume:	24
Number:	10
Page Range:	S. 3744 - 3756
Date:	2010
Publisher:	FEDERATION AMER SOC EXP BIOL
Place of Publication:	BETHESDA
ISSN:	0892-6638
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language OF-FUNCTION MUTATIONS; DEFICIENT MICE; CROSS-LINKING; PROTEINASE-INHIBITOR; EPITHELIAL-CELLS; REACTIVE-SITE; TRANSGLUTAMINASE; ICHTHYOSIS; GENE; DIFFERENTIATION Multiple languages Biochemistry & Molecular Biology; Biology; Cell Biology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/49550