人类遗传疾病和动物模型的研究表明,间质蛋白酶在表皮分化后期与前丝蛋白加工和脱屑相关的蛋白水解过程中起着至关重要的作用。人皮肤组织分布和酶原激活状态,然而,表明皮肤中的matriptase生理功能更可能在于基底层和棘层中角质形成细胞的增殖和分化。ARIH患者皮肤中几种终末分化标记的棘皮病具有扩张的棘层,强度和表达模式缺乏显着变化,支持间质蛋白酶在分化的早期而不是晚期阶段的作用。除了组织分布,差异亚细胞定位进一步限制了细胞外蛋白裂解酶蛋白水解活性进入细胞溶质非膜结合的角质透明素颗粒的能力,其中发生profilaggrin处理。活性蛋白裂解酶的寿命很短,这是由严格控制的酶原激活产生的,被HAI-1快速抑制,并从细胞表面脱落,表明活性蛋白蛋白酶可能通过其底物上的有限蛋白水解来执行生理功能,根据需要,而不是通过连续的散装过程。我们,在这里,回顾这些生化蛋白裂解酶蛋白水解活性的时空控制,细胞,和组织水平。基于对间质蛋白酶活性如何调节的深入理解,我们认为,间质蛋白酶的蛋白水解活性与前丝蛋白的加工和脱屑没有直接关系。与间质蛋白酶缺乏相关的表皮终末分化缺陷可能是继发性的,并且是由于分化早期的推定破坏所致。
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.