The Intramembrane Protease SPPL2A Is Critical for Tooth Enamel Formation
The Intramembrane Protease SPPL2A Is Critical for Tooth Enamel Formation
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DOI：
10.1002/jbmr.1895
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发表时间：
2013-07-01
影响因子：
6.2
通讯作者：
Schroeder, Bernd
中科院分区：
文献类型：
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作者：
Bronckers, Antonius L. J. J.;Gueneli, Nur;Schroeder, Bernd
膜内蛋白酶在信号转导和膜蛋白周转中起重要作用。信号肽肽酶样2a（SPPL 2A）是一种存在于溶酶体/晚期内体中的早老素同源物，切割II型定向跨膜蛋白。我们最近确定SPPL 2A作为主要组织相容性复合体II（MHCII）的不变链（CD 74）的控制营业额和功能的酶，并证明这一过程对B细胞发育至关重要。令人惊讶的是，我们发现SPPL 2A对于牙釉质的形成至关重要。在Sppl 2a基因敲除小鼠中，萌出的门牙的釉质是白垩色的白色，并且在萌出后迅速侵蚀。SPPL 2A在分泌期和成熟期的釉质上皮中均有表达。Sppl 2a-/-切牙中釉质的矿物质含量是不均匀的，并且与野生型小鼠相比减少了约20%，其中在近中侧减少最明显。通常，在敲出切牙中观察到牙釉质层的破坏和最表层牙釉质层的局部分离，导致牙釉质表面不均匀。在Sppl 2a敲除小鼠中，分泌期成釉细胞的形态和功能与野生型小鼠没有明显不同。然而，成熟阶段的成釉细胞显示出降低的高度和特征性的成釉细胞层的波动与局部的细胞粘附到外釉。这反映在蛋白质釉质基质的延迟和不完全吸收中。因此，我们得出结论，SPPL 2A的膜内蛋白水解是必不可少的维持成釉细胞的细胞内稳态。由于SPPL 2A活性的调节似乎是消耗B细胞和治疗自身免疫的有吸引力的治疗靶点，因此应将对牙釉质形成的干扰作为药理学SPPL 2A抑制剂在人体中的可能不良作用进行研究。
Intramembrane proteases are critically involved in signal transduction and membrane protein turnover. Signal-peptide-peptidase-like 2a (SPPL2A), a presenilin-homologue residing in lysosomes/late endosomes, cleaves type II-oriented transmembrane proteins. We recently identified SPPL2A as the enzyme controlling turnover and functions of the invariant chain (CD74) of the major histocompatibility complex II (MHCII) and demonstrated critical importance of this process for B cell development. Surprisingly, we found that SPPL2A is critical for formation of dental enamel. In Sppl2a knockout mice, enamel of the erupted incisors was chalky white and rapidly eroded after eruption. SPPL2A was found to be expressed in enamel epithelium during secretory and maturation stage amelogenesis. Mineral content of enamel in Sppl2a-/- incisors was inhomogeneous and reduced by approximate to 20% compared to wild-type mice with the most pronounced reduction at the mesial side. Frequently, disruption of the enamel layer and localized detachment of the most superficial enamel layer was observed in the knockout incisors leading to an uneven enamel surface. In Sppl2a null mice, morphology and function of secretory stage ameloblasts were not noticeably different from that of wild-type mice. However, maturation stage ameloblasts showed reduced height and a characteristic undulation of the ameloblast layer with localized adherence of the cells to the outer enamel. This was reflected in a delayed and incomplete resorption of the proteinaceous enamel matrix. Thus, we conclude that intramembrane proteolysis by SPPL2A is essential for maintaining cellular homeostasis of ameloblasts. Because modulation of SPPL2A activity appears to be an attractive therapeutic target to deplete B cells and treat autoimmunity, interference with tooth enamel formation should be investigated as a possible adverse effect of pharmacological SPPL2A inhibitors in humans.