German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
Neuroproteomics, School of Medicine, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
EMBO Mol Med. 2022 Oct 10;14(10):e16084. doi: 10.15252/emmm.202216084. Epub 2022 Sep 7.
Fn14 is a cell surface receptor with key functions in tissue homeostasis and injury but is also linked to chronic diseases. Despite its physiological and medical importance, the regulation of Fn14 signaling and turnover is only partly understood. Here, we demonstrate that Fn14 is cleaved within its transmembrane domain by the protease γ-secretase, resulting in secretion of the soluble Fn14 ectodomain (sFn14). Inhibition of γ-secretase in tumor cells reduced sFn14 secretion, increased full-length Fn14 at the cell surface, and enhanced TWEAK ligand-stimulated Fn14 signaling through the NFκB pathway, which led to enhanced release of the cytokine tumor necrosis factor. γ-Secretase-dependent sFn14 release was also detected ex vivo in primary tumor cells from glioblastoma patients, in mouse and human plasma and was strongly reduced in blood from human cancer patients dosed with a γ-secretase inhibitor prior to chimeric antigen receptor (CAR)-T-cell treatment. Taken together, our study demonstrates a novel function for γ-secretase in attenuating TWEAK/Fn14 signaling and suggests the use of sFn14 as an easily measurable pharmacodynamic biomarker to monitor γ-secretase activity in vivo.
Fn14 是一种细胞表面受体，在组织稳态和损伤中具有关键功能，但也与慢性疾病有关。尽管 Fn14 具有生理和医学上的重要性，但对其信号转导和周转的调节了解甚少。在这里，我们证明 Fn14 在其跨膜结构域内被蛋白酶 γ-分泌酶切割，导致可溶性 Fn14 胞外结构域 (sFn14) 的分泌。肿瘤细胞中 γ-分泌酶的抑制减少了 sFn14 的分泌，增加了细胞表面全长 Fn14 的表达，并通过 NFκB 途径增强了 TWEAK 配体刺激的 Fn14 信号转导，从而增强了细胞因子肿瘤坏死因子的释放。在来自胶质母细胞瘤患者的原代肿瘤细胞、小鼠和人血浆的体外实验中也检测到了 γ-分泌酶依赖性 sFn14 释放，并且在接受嵌合抗原受体 (CAR)-T 细胞治疗前用 γ-分泌酶抑制剂给药的人类癌症患者的血液中 sFn14 释放显著减少。综上所述，我们的研究证明了 γ-分泌酶在减弱 TWEAK/Fn14 信号中的新功能，并表明可以将 sFn14 用作可测量的药效动力学生物标志物，以监测体内 γ-分泌酶活性。
