Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, W412 Research Building 3970 Reservoir Road NW, Washington, DC, 20057, USA.
Department of Biochemistry National Defense Medical Center, Taipei, 11490, Taiwan.
Hum Cell. 2020 Jul;33(3):459-469. doi: 10.1007/s13577-020-00361-7. Epub 2020 Apr 18.
Studies of human genetic disorders and animal models indicate that matriptase plays essential roles in proteolytic processes associated with profilaggrin processing and desquamation at late stages of epidermal differentiation. The tissue distribution profile and zymogen activation status in human skin, however, suggests that matriptase physiological function in the skin more likely lies in the proliferating and differentiating keratinocytes in the basal and spinous layers. Marked acanthosis with expanded spinous layer and lack of significant changes in intensity and expression pattern for several terminal differentiation markers in the skin of ARIH patients support matriptase's role in earlier rather than the later stages of differentiation. In addition to the tissue distribution, differential subcellular localization further limits the ability of extracellular matriptase proteolytic activity to access the cytosolic non-membrane-bound keratohyalin granules, in which profilaggrin processing occurs. The short lifespan of active matriptase, which results from tightly controlled zymogen activation, rapid inhibition by HAI-1, and shedding from cell surface, indicates that active matriptase likely performs physiological functions via limited proteolysis on its substrates, as needed, rather than via a continuous bulk process. We, here, review these spatiotemporal controls of matriptase proteolytic activity at the biochemical, cellular, and tissue level. Based on this in-depth understanding of how matriptase activity is regulated, we argue that there is no direct involvement of matriptase proteolytic activity in profilaggrin processing and desquamation. The defects in epidermal terminal differentiation associated with matriptase deficiency are likely secondary and are due to putative disruption at earlier stages of differentiation.
人类遗传疾病和动物模型的研究表明，丝氨酸蛋白酶在与原丝聚蛋白加工和表皮分化晚期脱屑相关的蛋白水解过程中发挥重要作用。然而，人皮肤中的组织分布特征和酶原激活状态表明，丝氨酸蛋白酶在皮肤中的生理功能更可能在于基底层和棘层中的增殖和分化角蛋白细胞。ARIH 患者皮肤中的棘层明显肥大，几个终末分化标志物的强度和表达模式没有明显变化，这支持丝氨酸蛋白酶在分化的早期而不是晚期发挥作用。除了组织分布外，差异亚细胞定位进一步限制了细胞外丝氨酸蛋白酶的蛋白水解活性对细胞溶质中非膜结合角蛋白颗粒（原丝聚蛋白加工发生于此）的可及性。活性丝氨酸蛋白酶的短寿命是由于其酶原激活的严格控制、被 HAI-1 快速抑制以及从细胞表面脱落，这表明活性丝氨酸蛋白酶可能通过有限的蛋白水解作用来执行生理功能，如其底物所需，而不是通过连续的批量过程。我们在这里回顾了丝氨酸蛋白酶蛋白水解活性在生化、细胞和组织水平上的时空控制。基于对丝氨酸蛋白酶活性如何受到调节的深入了解，我们认为丝氨酸蛋白酶蛋白水解活性与原丝聚蛋白加工和脱屑没有直接关系。与丝氨酸蛋白酶缺乏相关的表皮终末分化缺陷可能是继发的，是由于分化早期的潜在破坏。
