Details

Autor(en) / Beteiligte

• Zeeuwen, Patrick L.J.M
• van Vlijmen-Willems, Ivonne M.J.J
• Cheng, Tsing
• Rodijk-Olthuis, Diana
• Hitomi, Kiyotaka
• Hara-Nishimura, Ikuko
• John, Susan
• Smyth, Neil
• Reinheckel, Thomas
• Hendriks, Wiljan J.A.J
• Schalkwijk, Joost

Titel

cystatin M/E-cathepsin L balance is essential for tissue homeostasis in epidermis, hair follicles, and cornea

Ist Teil von

• The FASEB journal, 2010-10, Vol.24 (10), p.3744-3755

Ort / Verlag

United States: The Federation of American Societies for Experimental Biology

Erscheinungsjahr

2010

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.