signaling flux redistribution at toll-like receptor pathway junctionstoll样受体通路连接信号流量重新分配.pdfVIP

Signaling Flux Redistribution at Toll-Like Receptor Pathway Junctions 1 2 3 1 4 1 Kumar Selvarajoo *, Yasunari Takada , Jin Gohda , Mohamed Helmy , Shizuo Akira , Masaru Tomita , 1 3 2 Masa Tsuchiya , Jun-ichiro Inoue , Koichi Matsuo * 1 Institute for Advanced Biosciences, Keio University, Tsuruoka, Japan, 2 Department of Microbiology and Immunology, School of Medicine, Keio University, Tokyo, Japan, 3 Division of Cellular and Molecular Biology, Institute of Medical Science, The University of Tokyo, Tokyo, Japan, 4 Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan Abstract Various receptors on cell surface recognize specific extracellular molecules and trigger signal transduction altering gene expression in the nucleus. Gain or loss-of-function mutations of one molecule have shown to affect alternative signaling pathways with a poorly understood mechanism. In Toll-like receptor (TLR) 4 signaling, which branches into MyD88- and TRAM-dependent pathways upon lipopolysaccharide (LPS) stimulation, we investigated the gain or loss-of-function mutations of MyD88. We predict, using a computational model built on the perturbation-response approach and the law of mass conservation, that removal and addition of MyD88 in TLR4 activation, enhances and impairs, respectively, the alternative TRAM-dependent pathway through signaling flux redistribution (SFR) at pathway branches. To verify SFR, we treated MyD88-deficient macrophages with LPS and observed enhancement of TRAM-dependent pathway based on increas