Dual Cleavage of Neuregulin 1 Type III by BACE1 and ADAM17 Liberates Its EGF-Like Domain and Allows Paracrine Signaling
Dual Cleavage of Neuregulin 1 Type III by BACE1 and ADAM17 Liberates Its EGF-Like Domain and Allows Paracrine Signaling
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DOI：
10.1523/jneurosci.3372-12.2013
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发表时间：
2013-05-01
影响因子：
5.3
通讯作者：
Haass, Christian
中科院分区：
文献类型：
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作者：
Fleck, Daniel;van Bebber, Frauke;Haass, Christian
细胞表面蛋白的蛋白水解脱落产生参与多种信号传导途径的旁分泌信号。 III 型神经调节蛋白 1 (NRG1) 参与周围神经系统的髓鞘形成，需要 ADAM 家族和 BACE1 的蛋白酶进行蛋白水解激活。这些蛋白酶是预防阿尔茨海默病的主要治疗靶点，因为它们还参与神经毒性淀粉样β-肽的蛋白水解生成。因此，对其生理底物的鉴定和功能研究对于防止不良副作用至关重要。在这里，我们研究了 NRG1 III 型的蛋白水解加工，并证明胞外域可以被三种不同的脱落酶（即 ADAM10、ADAM17 和 BACE1）切割。令人惊讶的是，我们不仅发现了 ADAM10、ADAM17 和 BACE1 C 端对表皮生长因子 (EGF) 样结构域的切割（据信该结构域在信号传导中发挥着关键作用），而且还发现了 ADAM17 和 BACE1 N 端对该结构域的其他切割位点。 EGF 样结构域 N 端和 C 端位点的蛋白水解加工导致该结构域从 III 型 NRG1 中分泌。可溶性 EGF 样结构域具有功能活性，可在组织培养测定中刺激 ErbB3 信号传导。此外，可溶性 EGF 样结构域能够挽救缺乏 BACE1 的斑马鱼突变体的髓鞘形成不足。我们的数据表明，NRG1 III 型依赖性髓鞘形成不仅受膜保留的 NRG1 III 型控制，而且还通过 EGF 样结构域的蛋白水解释放以旁分泌方式控制。
Proteolytic shedding of cell surface proteins generates paracrine signals involved in numerous signaling pathways. Neuregulin 1 (NRG1) type III is involved in myelination of the peripheral nervous system, for which it requires proteolytic activation by proteases of the ADAM family and BACE1. These proteases are major therapeutic targets for the prevention of Alzheimer's disease because they are also involved in the proteolytic generation of the neurotoxic amyloid beta-peptide. Identification and functional investigation of their physiological substrates is therefore of greatest importance in preventing unwanted side effects. Here we investigated proteolytic processing of NRG1 type III and demonstrate that the ectodomain can be cleaved by three different sheddases, namely ADAM10, ADAM17, and BACE1. Surprisingly, we not only found cleavage by ADAM10, ADAM17, and BACE1 C-terminal to the epidermal growth factor (EGF)-like domain, which is believed to play a pivotal role in signaling, but also additional cleavage sites for ADAM17 and BACE1 N-terminal to that domain. Proteolytic processing at N- and C-terminal sites of the EGF-like domain results in the secretion of this domain from NRG1 type III. The soluble EGF-like domain is functionally active and stimulates ErbB3 signaling in tissue culture assays. Moreover, the soluble EGF-like domain is capable of rescuing hypomyelination in a zebrafish mutant lacking BACE1. Our data suggest that NRG1 type III-dependent myelination is not only controlled by membrane-retained NRG1 type III, but also in a paracrine manner via proteolytic liberation of the EGF-like domain.