Oortveld Merel A W, van Vlijmen-Willems Ivonne M J J, Kersten Ferry F J, Cheng Tsing, Verdoes Martijn, van Erp Piet E J, Verbeek Sjef, Reinheckel Thomas, Hendriks Wiljan J A J, Schalkwijk Joost, Zeeuwen Patrick L J M
Department of Dermatology, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
FASEB J. 2017 Oct;31(10):4286-4294. doi: 10.1096/fj.201700267R. Epub 2017 Jun 8.
Deficiency of the cysteine protease inhibitor cystatin M/E (Cst6) in mice leads to disturbed epidermal cornification, impaired barrier function, and neonatal lethality. We report the rescue of the lethal skin phenotype of (Cst6-deficient; ) mice by transgenic, epidermis-specific, reexpression of Cst6 under control of the human involucrin (INV) promoter. Rescued Tg(INV-) mice survive the neonatal phase, but display severe eye pathology and alopecia after 4 mo. We observed keratitis and squamous metaplasia of the corneal epithelium, comparable to mice, as we have reported in other studies. We found the INV promoter to be active in the hair follicle infundibulum; however, we did not observe Cst6 protein expression in the lower regions of the hair follicle in Tg(INV-) mice. This result suggests that unrestricted activity of proteases is involved in disturbance of hair follicle biology, eventually leading to baldness. Using quenched activity-based probes, we identified mouse cathepsin B (CtsB), which is expressed in the lower regions of the hair follicle, as an additional target of mouse Cst6. These data suggest that Cst6 is necessary to control CtsB activity in hair follicle morphogenesis and highlight Cst6-controlled proteolytic pathways as targets for preventing hair loss.-Oortveld, M. A. W., van Vlijmen-Willems, I. M. J. J., Kersten, F. F. J., Cheng, T., Verdoes, M., van Erp, P. E. J., Verbeek, S., Reinheckel, T., Hendriks, W. J. A. J., Schalkwijk, J., Zeeuwen, P. L. J. M. Cathepsin B as a potential cystatin M/E target in the mouse hair follicle.
小鼠中半胱氨酸蛋白酶抑制剂胱抑素M/E（Cst6）的缺乏会导致表皮角质化紊乱、屏障功能受损以及新生小鼠死亡。我们报道了通过在人内披蛋白（INV）启动子控制下进行转基因、表皮特异性Cst6重新表达，挽救了（Cst6缺陷型；）小鼠的致死性皮肤表型。获救的Tg(INV-)小鼠在新生期存活下来，但在4个月后出现严重的眼部病变和脱发。我们观察到角膜上皮的角膜炎和鳞状化生，与小鼠相似，正如我们在其他研究中所报道的。我们发现INV启动子在毛囊漏斗部有活性；然而，我们在Tg(INV-)小鼠的毛囊下部未观察到Cst6蛋白表达。这一结果表明蛋白酶的无限制活性参与了毛囊生物学的紊乱，最终导致脱发。使用基于活性淬灭的探针，我们确定在毛囊下部表达的小鼠组织蛋白酶B（CtsB）是小鼠Cst6的另一个靶点。这些数据表明Cst6对于在毛囊形态发生过程中控制CtsB活性是必要的，并突出了Cst6控制的蛋白水解途径作为预防脱发的靶点。-奥尔特维尔德，M. A. W.，范·弗利门-威廉姆斯，I. M. J. J.，克尔斯滕，F. F. J.，程，T.，韦尔德斯，M.，范·埃尔普，P. E. J.，韦贝克，S.，莱因黑克尔，T.，亨德里克斯，W. J. A. J.，沙尔克维克，J.，泽温，P. L. J. M. 组织蛋白酶B作为小鼠毛囊中潜在的胱抑素M/E靶点。
