The intramembrane protease γ-secretase is a hetero-tetrameric protein complex with presenilin as the catalytic subunit and cleaves its membrane protein substrates within their single transmembrane domains. γ-Secretase is well known for its role in Notch signalling and in Alzheimer’s disease, where it catalyzes the formation of the pathogenic amyloid β (Aβ) peptide. However, in the 21 years since its discovery many more substrates and substrate candidates of γ-secretase were identified. Although the physiological relevance of the cleavage of many substrates remains to be studied in more detail, the substrates demonstrate a broad role for γ-secretase in embryonic development, adult tissue homeostasis, signal transduction and protein degradation. Consequently, chronic γ-secretase inhibition may cause significant side effects due to inhibition of cleavage of multiple substrates. This review provides a list of 149 γ-secretase substrates identified to date and highlights by which expeirmental approach substrate cleavage was validated. Additionally, the review lists the cleavage sites where they are known and discusses the functional implications of γ-secretase cleavage with a focus on substrates identified in the recent past, such as CHL1, TREM2 and TNFR1. A comparative analysis demonstrates that γ-secretase substrates mostly have a long extracellular domain and require ectodomain shedding before γ-secretase cleavage, but that γ-secretase is also able to cleave naturally short substrates, such as the B cell maturation antigen. Taken together, the list of substrates provides a resource that may help in the future development of drugs inhibiting or modulating γ-secretase activity in a substrate-specific manner.

膜内蛋白酶γ-分泌酶是一种以早老素为催化亚基的异四聚体蛋白复合物，可在其单个跨膜结构域内切割其膜蛋白底物。γ-秘密酶因其在Notch信号传导和阿尔茨海默氏病中的作用而闻名，在那里它催化致病性淀粉样β（Aβ）肽的形成。然而，自发现以来的21年中，发现了更多的底物和γ-分泌酶的底物候选物。尽管许多底物裂解的生理相关性有待进一步研究，但底物显示出γ-分泌酶在胚胎发育，成人组织稳态，信号转导和蛋白质降解中的广泛作用。所以，慢性γ-分泌酶抑制作用可能由于抑制多种底物的裂解而引起明显的副作用。这篇综述提供了迄今为止已鉴定的149种γ-分泌酶底物的清单，并重点介绍了通过实验方法验证底物裂解的方法。此外，该综述列出了已知的切割位点，并讨论了γ-分泌酶切割的功能含义，重点是最近鉴定的底物，例如CHL1，TREM2和TNFR1。对比分析表明，γ-分泌酶底物大部分具有较长的胞外域，并且在切割γ-分泌酶之前需要胞外域脱落，但是γ-分泌酶也能够裂解天然短的底物，例如B细胞成熟抗原。在一起