跨膜丝氨酸蛋白酶TMPRSS3与遗传性耳聋

A Member of Ⅱ Transmembrane Serine,TMPRSS3 and Hereditary Deafness

跨膜丝氨酸蛋白酶TMPRSS3(transmembrane protease,serine3)属于TTSPs(typeⅡtransmembrane serine proteases)家族成员,在分子结构上,TMPRSS3具有典型的TTSPs结构域,如丝氨酸蛋白酶、LDLRA、SRCR等.TMPRSS3有不同的蛋白异构体,其中异构体A是体内最主要的存在形式,主要在内耳表达,亚细胞水平定位于内质网膜上,TMPRSS3基因缺陷是遗传性耳聋DFNB8/10的遗传基础,因此目前对TMPRSS3的功能研究主要集中在听觉系统方面,此外蛋白异构体D还可能是卵巢癌的生物学标志物.TMPRSS3是迄今为止发现的第一个基因突变能引起耳聋的蛋白酶,表明听觉通路上的某些关键调控因子可能作为它的生理学底物被水解激活,从而介导相应的信号转导途径,但它激活了哪些信号通道,目前尚不清楚.借鉴mCAP(mouse channel activating protease)的功能预测ENaC(epithelial sodium channel)可能是TMPRSS3的作用底物,推测TMPRSS3参与内耳Na+平衡调控,但仍有待于体内实验证实.当前酶学领域研究技术的革新发展,尤其酶降解组学的应用,为认识蛋白酶TMPRSS3的功能及其复杂的分子调控机制提供了新的捷径.

TMPRSS3 （transmembrane protease, serine 3） is a member of Ⅱ transmembrane serine proteases （TTSPs）, and like the other members of this family, it contains typical domains including a serine protease domain, a transmembrane domain, a LDL receptor-like domain （LDLRA）, and a scavenger receptor cysteine-rich domain （SRCR）. Four alternative protein isoforms have been described, and isoform A is thought to be primary isoform which is expressed in many tissues, especially in the cochlea. TMPRSS3 protein is primarily localized in the endoplasmic reticulum membranes where it may be anchored by its transmembrane domain. TMPRSS3 is mutated in non-syndromic autosomal recessive deafness （DFNB8/10）. Therefore TMPRSS3 is thought to be involved in the development and maintenance of the inner ear, and isoform D may be proposed as a novel diagnostic marker in ovarian carcinoma. TMPRSS3 protein is the first protease which mutation could lead to deafness. These data indicate that important signaling pathways in the inner ear are controlled by proteolytic cleavage. However, it is not clear about TMPRSS3 substrates and its function. The epithelial amiloride-sensitive sodium channel （ENaC） which is regulated by membrane-bound channel activating serine proteases （CAPs）, a member of TTSPs, may be a potential substrate of TMPRSS3, but this hypothesis is still to be verified in vivo. With the development of protease research and the application ofprotease proteomics, substrate degradomes of a protease may therefore represent an important tool for the research of TMPRSS3 function and its molecular mechanism.