Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, U.S.A.
Programs of Pharmacology, Weill Graduate School of Medical Sciences of Cornell University, New York, NY, U.S.A.
Biochem Soc Trans. 2023 Aug 31;51(4):1597-1610. doi: 10.1042/BST20221445.
Innate immunity is the first line of defense against pathogens, alerting the individual cell and surrounding area to respond to this potential invasion. γ-secretase is a transmembrane protease complex that plays an intricate role in nearly every stage of this innate immune response. Through regulation of pattern recognition receptors (PRR) such as TREM2 and RAGE γ-secretase can modulate pathogen recognition. γ-secretase can act on cytokine receptors such as IFNαR2 and CSF1R to dampen their signaling capacity. While γ-secretase-mediated regulated intramembrane proteolysis (RIP) can further moderate innate immune responses through downstream signaling pathways. Furthermore, γ-secretase has also been shown to be regulated by the innate immune system through cytokine signaling and γ-secretase modulatory proteins such as IFITM3 and Hif-1α. This review article gives an overview of how γ-secretase is implicated in innate immunity and the maintenance of its responses through potentially positive and negative feedback loops.
先天免疫是抵御病原体的第一道防线，它会提醒单个细胞和周围区域对这种潜在入侵做出反应。γ-分泌酶是一种跨膜蛋白酶复合物，在先天免疫反应的几乎每个阶段都发挥着复杂的作用。通过调节模式识别受体（PRR），如 TREM2 和 RAGE，γ-分泌酶可以调节病原体的识别。γ-分泌酶可以作用于细胞因子受体，如 IFNαR2 和 CSF1R，以抑制其信号转导能力。而 γ-分泌酶介导的调节膜内蛋白水解（RIP）可以通过下游信号通路进一步调节先天免疫反应。此外，先天免疫系统还通过细胞因子信号和γ-分泌酶调节蛋白（如 IFITM3 和 Hif-1α）来调节 γ-分泌酶。这篇综述文章概述了 γ-分泌酶如何参与先天免疫以及通过潜在的正反馈和负反馈环来维持其反应。
