| First Author | Zeeuwen PL | Year | 2010 |
| Journal | FASEB J | Volume | 24 |
| Issue | 10 | Pages | 3744-55 |
| PubMed ID | 20495178 | Mgi Jnum | J:165312 |
| Mgi Id | MGI:4836818 | Doi | 10.1096/fj.10-155879 |
| Citation | Zeeuwen PL, et al. (2010) The cystatin M/E-cathepsin L balance is essential for tissue homeostasis in epidermis, hair follicles, and cornea. FASEB J 24(10):3744-55 |
| abstractText | 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. |
