The cystatin M/E-cathepsin L balance is essential for tissue homeostasis in epidermis, hair follicles, and cornea
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. and Schalkwijk, Joost (2010) The cystatin M/E-cathepsin L balance is essential for tissue homeostasis in epidermis, hair follicles, and cornea. FASEB Journal (doi:10.1096/fj.10-155879).
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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.
|Divisions:||University Structure - Pre August 2011 > School of Biological Sciences
|Date Deposited:||30 Jun 2010 08:29|
|Last Modified:||01 Jun 2011 17:41|
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