Novel regulatory themes in immune cell signal transduction: Physiological functions of death receptor endocytosis
Final Report Abstract
The aim of this research proposal was to understand fundamental principals in the regulation and biology of receptor signal transduction. In this study, we investigated the role of the endocytic membrane trafficking network in immune receptor signaling and its physiological relevance for immune responses. Specifically, we revealed an unexpected function of endosomal receptor trafficking in the regulation of specific Toll-like receptor (TLR)-signaling pathways and inflammatory responses. The study thus defines a higher level of complexity in receptor signaling and immune regulation, that goes beyond simple receptor signaling cascades. In our study, we showed that lysosomal trafficking regulator Lyst links endolysosomal organization to the selective control of Toll-like receptor 3 (TLR3)- and TLR4-mediated pro-inflammatory responses. Consequently, Lyst-mutant mice showed increased susceptibility to bacterial infection and were largely resistant to endotoxin-induced septic shock. Mechanistic analysis revealed that Lyst specifically controls TLR3- and TLR4-induced TRIF signaling pathways which are specifically activated at intracellular endosomal compartments. Loss of functional Lyst leads to dysregulated endosomal/lysosomal membrane trafficking, resulting in a failure to form an activation-induced Rab7+ endosomal compartment. This specific Rab7+ compartment was further demonstrated to serve as a major site for active endosomal TRIF signaling events, thus linking lysosomal trafficking to specific TLR signaling pathways. The immunoregulatory role of Lyst on TLR-signaling pathways was confirmed in human cells by CRISPR/Cas9-mediated gene inactivation. As mutations in LYST cause human Chédiak-Higashi syndrome, a severe immunodeficiency, our findings also contribute to a better understanding of human disease mechanisms.
Publications
- Lysosomal trafficking regulator Lyst controls innate immune cell signalling and function: regulation of TLR-mediated TRIF signalling and control of mast cell-mediated allergic reactions. Hannover Medical School, 2017
Andreas Westphal
- Lysosomal trafficking regulator Lyst links membrane trafficking to toll-like receptormediated inflammatory responses. The Journal of Experimental Medicine. 2017 Jan;214(1):227-244
Westphal A, Cheng W, Yu J, Grassl G, Krautkrämer M, Holst O, Föger N, Lee KH
(See online at https://doi.org/10.1084/jem.20141461)
