A new master adaptor protein for Toll-like Receptor signalling (2016–2019)
The Toll-like Receptor (TLR) family of pattern recognition receptors enables cells to sense danger in the form of infection, tissue damage and/or dysregulated metabolism. Dysregulated TLR activation drives pathology in a diverse array of inflammation-related diseases including autoimmune disease, neurodegenerative disease, cardiovascular disease and cancer. Studies of TLR signalling have focused almost exclusively on receptor-mediated activation of Toll/Interleukin-1 receptor (TIR) domain-containing adaptor proteins such as Mal and MyD88 to generate signalling outputs and inflammatory responses. We have recently identified a new adaptor protein, SCIMP (SLP65/SLP76, Csk-Interacting Membrane Protein) for TLRs that redefines adaptor-TLR interactions. SCIMP mediates TLR phosphorylation, downstream TLR signalling and drives a sub-set of TLR-dependent inflammatory responses in macrophages. We now propose to precisely define the set of SCIMP-dependent TLR-inducible pro-inflammatory responses, delineate proximal signalling events and characterize in detail the direct interaction between TLR4 and SCIMP to enable us to develop tools to target this pathway. To do so, we will use biochemical approaches to study protein-protein interactions, cell biology experiments to examine SCIMP localization and functions, and screening assays to arrive at novel SCIMP inhibitors that will be interrogated in vitro and in vivo. The outcomes will provide a paradigm shift in our understanding of TLR signalling, and will generate exciting new opportunities for understanding the role of SCIMP in inflammation-related diseases, and potentially, for manipulating this pathway for therapeutic benefit.