Several integral membrane proteins undergo regulated intramembrane proteolysis (RIP), a tightly controlled process through which cells transmit information across and between intracellular compartments. RIP generates biologically active peptides by a series of proteolytic cleavage events carried out by two primary groups of enzymes: sheddases and intramembrane-cleaving proteases (iCLiPs). Following RIP, fragments of both pore-forming and non–pore-forming ion channel subunits, as well as immunoglobulin super family (IgSF) members, have been shown to translocate to the nucleus to function in transcriptional regulation. As an example, the voltage-gated sodium channel β1 subunit, which is also an IgSF-cell adhesion molecule (CAM), is a substrate for RIP. β1 RIP results in generation of a soluble intracellular domain, which can regulate gene expression in the nucleus. In this review, we discuss the proposed RIP mechanisms of voltage-gated sodium, potassium, and calcium channel subunits as well as the roles of their generated proteolytic products in the nucleus. We also discuss other RIP substrates that are cleaved by similar sheddases and iCLiPs, such as IgSF macromolecules, including CAMs, whose proteolytically generated fragments function in the nucleus. Importantly, dysfunctional RIP mechanisms are linked to human disease. Thus, we will also review how understanding RIP events and subsequent signaling processes involving ion channel subunits and IgSF proteins may lead to the discovery of novel therapeutic targets.

中文翻译：

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靶向电压门控离子通道亚基和细胞粘附分子调节膜内蛋白水解机制的治疗潜力

几种整合膜蛋白经历受调节的膜内蛋白水解（RIP），这是一个严格控制的过程，细胞通过该过程在细胞内区室之间传递信息。RIP 通过两类主要酶进行的一系列蛋白水解裂解事件生成生物活性肽：脱落酶和膜内裂解蛋白酶 (iCLiP)。RIP 后，成孔和非成孔离子通道亚基片段以及免疫球蛋白超家族 (IgSF) 成员已被证明易位至细胞核，在转录调节中发挥作用。例如，电压门控钠通道β 1 亚基也是一种 IgSF 细胞粘附分子 (CAM)，是 RIP 的底物。β 1 RIP 导致可溶性细胞内结构域的生成，该结构域可以调节细胞核中的基因表达。在这篇综述中，我们讨论了电压门控钠、钾和钙通道亚基的 RIP 机制以及它们在细胞核中产生的蛋白水解产物的作用。我们还讨论了被类似脱落酶和 iCLiP 切割的其他 RIP 底物，例如 IgSF 大分子，包括 CAM，其蛋白水解生成的片段在细胞核中发挥作用。重要的是，功能失调的 RIP 机制与人类疾病有关。因此，我们还将回顾了解 RIP 事件和涉及离子通道亚基和 IgSF 蛋白的后续信号传导过程如何导致新治疗靶点的发现。