Netzel-Arnett Sarah, Currie Brooke M, Szabo Roman, Lin Chen-Yong, Chen Li-Mei, Chai Karl X, Antalis Toni M, Bugge Thomas H, List Karin
Center for Vascular and Inflammatory Diseases and Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
J Biol Chem. 2006 Nov 3;281(44):32941-5. doi: 10.1074/jbc.C600208200. Epub 2006 Sep 15.
Recent gene ablation studies in mice have shown that matriptase, a type II transmembrane serine protease, and prostasin, a glycosylphosphatidylinositol-anchored membrane serine protease, are both required for processing of the epidermis-specific polyprotein, profilaggrin, stratum corneum formation, and acquisition of epidermal barrier function. Here we present evidence that matriptase acts upstream of prostasin in a zymogen activation cascade that regulates terminal epidermal differentiation and is required for prostasin zymogen activation. Enzymatic gene trapping of matriptase combined with prostasin immunohistochemistry revealed that matriptase was co-localized with prostasin in transitional layer cells of the epidermis and that the developmental onset of expression of the two membrane proteases was coordinated and correlated with acquisition of epidermal barrier function. Purified soluble matriptase efficiently converted soluble prostasin zymogen to an active two-chain form that formed SDS-stable complexes with the serpin protease nexin-1. Whereas two forms of prostasin with molecular weights corresponding to the prostasin zymogen and active prostasin were present in wild type epidermis, prostasin was exclusively found in the zymogen form in matriptase-deficient epidermis. These data suggest that matriptase, an autoactivating protease, acts upstream from prostasin to initiate a zymogen cascade that is essential for epidermal differentiation.
最近在小鼠身上进行的基因敲除研究表明，II型跨膜丝氨酸蛋白酶胃蛋白酶原激活酶和糖基磷脂酰肌醇锚定膜丝氨酸蛋白酶前列腺素，对于表皮特异性多蛋白丝聚蛋白原的加工、角质层形成以及表皮屏障功能的获得都是必需的。在此我们提供证据表明，胃蛋白酶原激活酶在调节表皮终末分化的酶原激活级联反应中作用于前列腺素上游，并且是前列腺素酶原激活所必需的。胃蛋白酶原激活酶的酶促基因捕获与前列腺素免疫组织化学相结合显示，胃蛋白酶原激活酶与前列腺素在表皮过渡层细胞中共定位，并且这两种膜蛋白酶的发育性表达起始是协调的，且与表皮屏障功能的获得相关。纯化的可溶性胃蛋白酶原激活酶能有效地将可溶性前列腺素酶原转化为活性双链形式，该形式与丝氨酸蛋白酶抑制因子nexin-1形成SDS稳定复合物。野生型表皮中存在两种分子量分别对应于前列腺素酶原和活性前列腺素的前列腺素形式，而在胃蛋白酶原激活酶缺陷的表皮中，前列腺素仅以酶原形式存在。这些数据表明，胃蛋白酶原激活酶作为一种自激活蛋白酶，在前列腺素上游起作用，启动一个对表皮分化至关重要的酶原级联反应。
