Lee Kong Chian School of Medicine, Nanyang Technological University, Clinical Science Building, 11 Mandalay Road, 10-01-01 M, Singapore, 308232, Singapore.
Interdisciplinary Graduate School (IGS), Nanyang Technological University, Singapore, Singapore.
Neuromolecular Med. 2020 Mar;22(1):1-24. doi: 10.1007/s12017-019-08556-4. Epub 2019 Jul 25.
Regulated intramembrane proteolysis (RIP) occurs in a cell when transmembrane proteins are cleaved by intramembrane proteases such as secretases to generate soluble protein fragments in the extracellular environment and the cytosol. In the cytosol, these soluble intracellular domains (ICDs) have local functions near the site of cleavage or in many cases, translocate to the nucleus to modulate gene expression. While the mechanism of RIP is relatively well studied, the fate and function of ICDs for most substrate proteins remain poorly characterized. In neurons, RIP occurs in various subcellular compartments including at the synapse. In this review, we summarize current research on RIP in neurons, focusing specifically on synaptic proteins where the presence and function of the ICDs have been reported. We also briefly discuss activity-driven processing of RIP substrates at the synapse and the cellular machinery that support long-distance transport of ICDs from the synapse to the nucleus. Finally, we describe future challenges in this field of research in the context of understanding the contribution of ICDs in neuronal function.
受调控的膜内蛋白水解（RIP）发生在细胞中，当跨膜蛋白被跨膜蛋白酶（如分泌酶）切割时，会在细胞外环境和细胞质中生成可溶性蛋白片段。在细胞质中，这些可溶性细胞内结构域（ICD）在切割部位附近具有局部功能，或者在许多情况下，易位到细胞核以调节基因表达。虽然 RIP 的机制已经得到了较为深入的研究，但大多数底物蛋白的 ICD 的命运和功能仍未得到充分描述。在神经元中，RIP 发生在各种亚细胞隔室中，包括突触。在这篇综述中，我们总结了神经元中 RIP 的研究现状，特别关注了已经报道了 ICD 存在和功能的突触蛋白。我们还简要讨论了突触处 RIP 底物的活性驱动加工以及支持 ICD 从突触到细胞核的远距离运输的细胞机制。最后，我们在理解 ICD 在神经元功能中的贡献的背景下，描述了该研究领域的未来挑战。
